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Dangerous Drugs & Medical Devices News & Commentary on Prescription Drug & Medical Device Lawsuits

Expert Report in Fleet Phospho-Soda Lawsuit

Posted in Misc. Drugs

This expert report discusses the actions that Fleet did and didn’t take with respect to Phospho-Soda and its association with kidney problems.  It comes from Bracey v. Fleet, and the expert is Suzanne Parisian.

31.) Dr. Caswell's statement to health care providers in his 2002 letter regarding post-marketing experience confirming the product as "safe and effective", incorrectly implies that Fleet Phospho-soda was approved for marketing by FDA through a New Drug Application (NDA) with a commitment for post marketing. He fails to more precisely inform health care providers that Fleet Phospho-soda, unlike competitor bowel preparation products marketed via approved NDAs, Fleet Phospho-soda remains on the market "grandfathered" as safe, able to support efficacy as an active ingredient with limited data and considered by FDA as "generally recognized as safe and effective"(GRASE). Despite the tome of the letter, Dr. Caswell was unaware when Fleet Phospho-soda had first become actively promoted for colon preparation. (Caswell April 5, 2006, Volume I testimony, page 124, lines 13-19). He indicated letter that there were only 40 USA based serious adverse events reported to Fleet from 1991 through 2001. However, Dr. Caswell was unfamiliar with the nature of those reports, unable to provide the types of procedures being performed when the events occurred, the dosing, type of populations involved or any other signal associated with possible increased risk. He also was unaware of methods of rehydration being used by patients in the adverse event reports. (Caswell April 5, 2006, Volume I testimony, page 125, lines 14-25).
32.) Fleet did not provide United States physicians with information described in the Australian Adverse Drug Reactions Bulletin, Vol. 16, No. 1 (February 1997) warning about the risks of electrolyte shifts with Fleet Phospho-soda. According to Dr. Caswell's testimony above, he considered the risks for electrolyte shifts with a single dose of Fleet Phospho-soda Solution as "known" since 1968. However, the Australian agency, unlike Dr. Caswell, felt that it was safety information which needed to be conveyed to health professionals in 1997. The Australian bulletin had been prepared by the Adverse Drug Reactions Advisory Committee (ADRAC) (Exhibit 122, CBFL-0000125-8). Heading 1. ELECTROLYTE DISTURBANCES WITH ORAL PHOSPHATE BOWEL PREPARATION.
In recent years, the use of oral sodium phosphate solution (Fleet Phospho-Soda Buffered Saline Laxative Mixture) as a bowel preparation for colonoscopy has become more common. Over the past 18 months, ADRAC has received three serious reports, two with fatal outcomes, highlighting severe electrolyte disturbances associated with this oral bowel cleansing solution. The product is available without prescription and can also be used as a laxative at a lower dose…..

Timothy Bracey & Brenda Bracey v. C.B. Fleet Holding Company, et al.

I. Qualifications

1) Since August 1995, I have been President and founder of MD Assist, Inc., a regulatory and medical consulting firm specializing in matters involving the United States Food and Drug Administration's regulation of products. I received my Medical Degree (M.D.) from the University of South Florida in 1978 and am Board Certified in Anatomic and Clinical Pathology. From 1991 to 1995, I served as a Commissioned Officer in the United States Public Health Service and achieved the rank of Commander. During this period, I was assigned to the Center for Devices and Radiological Health (CDRH) at the Food and Drug Administration (FDA). Concurrently, I was also assigned clinical responsibilities at the Armed Forces Institute of Pathology (AFIP), Office of the Medical Examiner for the Armed Forces, Washington, D.C.
2) From 1991 to 1993, I was a Medical Officer in the Office of Health Affairs (OHA), a staff office within the Center for Devices and Radiological Health, FDA. From March 1993 to December 1993, I was a Medical Officer in the Office of Device Evaluation (ODE), Division of Reproductive Abdominal, Ear, Nose and Throat, and Radiology, (DRAERD), FDA. From January 1994 through June 1995, I was Chief Medical Officer for DRAERD and ODE.
3) ODE, FDA is an Office responsible for the premarketing evaluation of product applications submitted by manufacturers to commercially market devices that are safe and effective within the United States. In ODE, I participated in the review of marketing
2. Mix 2 or 3 tablespoons Fleet(R) Phospho-soda(R) oral saline laxative with two or three 8 fl. oz. glasses of cold, clear liquid (one tablespoon of Fleet(R) Phospho-soda(R) oral saline laxative per glass). Drink two glasses within 20 minutes or three glasses within 30 minutes. Then follow with at least 24 fl. oz. of clear liquid.
22.) The information provided to physicians by Fleet in PDRs through the year 2006 still remains incomplete. Fleet has maintained its own internal policy to provide health care providers and patients with additional Fleet Phospho-Soda Bowel Preparation Instructions not present in the PDR. (Exhibit 114, 5/10/06; Exhibit 115 5/10/06 In Mind, Inc. Version dated 12/12/2003 — ACCU PREP Instructions; Exhibit 116, 5/10/06 In Mind Inc, 4/15/05; Exhibit 117 5/10/06 CBFL2-0002728-9). The instructions include the following administration and hydration information:
•Two days before your procedure, purchase 3 oz. of Fleet Phospho-soda.
•Follow the steps listed below, or as otherwise prescribed by your doctor on back.
•If you are taking medication (including aspirin or aspirin-containing products,) consult your doctor for additional instructions before beginning this procedure.
7:00 pm- Take Fleet Phospho-soda (See "How to take Fleet Phospho-soda" below)
Evening — Drink at least 3 more glasses (8 oz. each) of Clear Liquids (Then you may drink all the Clear Liquids you desire)…. Day of Exam
6:00 AM (or at least 3 hours before you leave for your exam) Take Fleet Phospho-soda (See "How to Take Fleet Phospho-Soda" below)…….
HOW TO TAKE FLEET PHOSPHO-SODA:
A) Mix 1 1/2 oz. (3 measuring tablespoons- NOT tableware) of Fleet Phospho-soda with at least 4 oz. of cold Clear Liquid (ginger ale, apple juice, Sprite, or 7-Up helps improve the taste) and drink. Follow with a
27.) Fleet did not provide US physicians and health care providers with the same important safety information and warnings about risks of Fleet Phospho-soda that its Canadian distributor, Johnson & Johnson/ Merck Pharmaceuticals, provided to Canadian Health Care Providers on March 15, 2002 (Exhibit 54, 4/6/06). In 2002, Canadian healthcare providers were informed that electrolyte shifts might occur in any patient both with and without risk factors if the maximum recommended dose of 45 mL in a 24-hour period was exceeded; adverse conditions were more likely to occur when more than one dose of 45 mL was given in 24-hour period; and the recommended maximum total daily dose for any indication for adults was 45 mL in a 24-hour period. The product was to be used with caution in all patients with impaired renal function, heart disease, acute myocardial infarction, unstable angina, pre-existing electrolyte imbalances, patients taking drugs that alter electrolyte levels, elderly or debilitated patients. The Canadian Adverse Drug Reaction Monitoring Program from 1987 to October 31, 2001 produced 10 domestic Canadian reports with 9 reports involving one or more risk factor. The reporting rates were determined based on spontaneously reported post-marketing adverse events and were thought to underestimate the true risk associated with the use of the drug. The Canadian reader was referred to the FDA's 2001 Science Backgrounder for further information. Fleet did not forward this same safety notification information on to United States health care providers.
28.) Fleet sent out a May 2002 letter to United States Health Professionals, signed by Dr. Michael Caswell, which is not a "safety notification" but rather a promotion for the "safety and effectiveness" of Fleet Phospho-soda for bowel preparation. The letter indicates on the first page of a two page letter that the two 45 mL dose regimen has been extensively studied and shown to be safe, a purgative dose with superior cleansing effectiveness, good patient compliance, safe, effective and inexpensive. The Canadian message of public health risk is completely lost. Fleet's letter contradicts the Canadian letter in that it indicates that only certain groups of patients are at increased risk. Fleet indicates that patients have problems with improper use or overdosage. There is no information provided to health care providers that patients are at increased risk of serious complications even with proper use of the product. For a health care professional to prescribe the product safely and effectively, they must know how to prescribe it correctly, something Fleet has avoiding doing. The message of the letter, the health care professional prescribing the product and improper patient selection, and not Fleet Phospho-soda, is responsible for complications. The letter repeats in almost every paragraph the same theme: Fleet Phospho-soda is "safe and effective."
29.) In Exhibit 55, 4/6/060, C.B. Fleet Company, Inc. sent out the following May, 2002 letter to United States Health Professionals. The letter was signed by Dr. Caswell, Director of Scientific and Medical Affairs, and stated the following:

Safe and Effective Use of Fleet Phospho-soda

Fleet Phospho-soda Oral Saline Laxative consists of Sodium Phosphates Oral Solution, USP. The product has been marketed since 1869, and hundreds of millions of doses have been administered safely and effectively for use as a laxative for treatment of occasional constipation and for use as a purgative for bowel cleansing prior to endoscopic and x-ray examinations and surgery.
The use of the product as a bowel purgative, two 45 mL doses, has been extensively studied. In these studies, use of Fleet Phospho-soda was shown to provide superior cleansing effectiveness, to result in a greater degree of patient compliance than other types of bowel preparations, and to be a safe, effective, and inexpensive method of preparation of the bowel for endoscopic examination and surgery. Representative clinical studies (references 1 to 21) supporting the safety and efficacy of the product can be found in the Bibliography at the end of this letter. As a result of its demonstrated safety and effectiveness, Fleet Phospho-soda has become a leading bowel purgative and is widely accepted for use by colonoscopists, surgeons, and other medical specialists.
Post-marketing experience has confirmed the product to be safe and effective. In the 11 years from 1991 through 2001, almost 28 million doses of 90 mL equivalents of the product were sold in the United States. During that time, only 40 USA-based serious adverse experience reports were reported to Fleet, to the FDA or in the published literature, resulting in a rate of about 1.5 serious adverse experiences per million doses sold. Although reporting systems can underreport the number of serious adverse events that occur, these figures demonstrate that serious adverse events with Fleet Phospho-soda are infrequent.

Important Information for Safe Use of Fleet Phospho-soda

To prescribe any product safely and effectively, you must know and understand its limitations, including contraindications, safety issues, and potential sequalae of use. To ensure safe and successful use of Fleet Phospho-soda as a bowel cleansing agent, please carefully review the following information before prescribing.
Fleet Phospho-soda can be safely and effectively used as a bowel-cleansing agent. However, it should not be used in some patients and should be used with caution in others. Since Fleet Phospho-soda contains sodium phosphates, there is a possibility of an effect on electrolyte and vascular volume; consequently serious side effects can occur, particularly if the product is improperly used…
Improper use or overdose of the product can result in decreased levels of calcium and potassium and elevated levels of sodium and phosphate. These electrolyte disturbances can result in acidosis, tetany, cardiac arrhythmias, dehydration, renal failure, hypovolemia, and, in rare cases, death in patients in whom the use of oral sodium phosphates is contraindicated or in patients at-risk. These conditions are more likely to occur where more than 45 mL of the product is given in less than a 24-hour period.
Healthcare professionals should consider obtaining baseline and post-treatment sodium, potassium, chloride, bicarbonate, calcium, phosphate, blood urea nitrogen, and creatinine values in at-risk patients for whom more than 45 mL of oral sodium phosphate in a 24-hour period is recommended.
In all patients, it is important to recommend additional clear fluids by mouth to prevent dehydration, and to ensure that no other sodium phosphate preparations are given concomitantly.
… Should you require further information, please refer to the product information in the Physicians' Desk Reference(R), call our Medical Affairs Department, weekdays between the hours of 7:45 a.m. and 4:30 p.m. EST, at 888- 999-9711, Ext 8278, or visit www.phosphosoda.com
30.) Fleet's 2002 letter indicated that electrolyte disturbances and in rare instances death, could result in patients in whom the use of oral sodium phosphate is contraindicated or in patients at-risk (Caswell April 5, 2006, Volume I testimony, page 121, lines 16-24). According to Dr. Caswell, Fleet's 2002 letter did not discuss the issue of electrolyte shifts as a result of administration of a single dose of Fleet Phospho-soda since that information had already been known since 1968. (Caswell April 5, 2006, Volume I testimony, page 123, lines 1-9). The Fleet 2002 letter also stated that the product had been marketed since 1869, which Dr. Caswell subsequently found out was an incorrect statement, when he learned the product had actually been marketed since 1893 as a laxative for treatment of constipation. (Caswell April 5, 2006, Volume I testimony, page 123, lines 14-24).
31.) Dr. Caswell's statement to health care providers in his 2002 letter regarding post-marketing experience confirming the product as "safe and effective", incorrectly implies that Fleet Phospho-soda was approved for marketing by FDA through a New Drug Application (NDA) with a commitment for post marketing. He fails to more precisely inform health care providers that Fleet Phospho-soda, unlike competitor bowel preparation products marketed via approved NDAs, Fleet Phospho-soda remains on the market "grandfathered" as safe, able to support efficacy as an active ingredient with limited data and considered by FDA as "generally recognized as safe and effective"(GRASE). Despite the tome of the letter, Dr. Caswell was unaware when Fleet Phospho-soda had first become actively promoted for colon preparation. (Caswell April 5, 2006, Volume I testimony, page 124, lines 13-19). He indicated letter that there were only 40 USA based serious adverse events reported to Fleet from 1991 through 2001. However, Dr. Caswell was unfamiliar with the nature of those reports, unable to provide the types of procedures being performed when the events occurred, the dosing, type of populations involved or any other signal associated with possible increased risk. He also was unaware of methods of rehydration being used by patients in the adverse event reports. (Caswell April 5, 2006, Volume I testimony, page 125, lines 14-25).
32.) Fleet did not provide United States physicians with information described in the Australian Adverse Drug Reactions Bulletin, Vol. 16, No. 1 (February 1997) warning about the risks of electrolyte shifts with Fleet Phospho-soda. According to Dr. Caswell's testimony above, he considered the risks for electrolyte shifts with a single dose of Fleet Phospho-soda Solution as "known" since 1968. However, the Australian agency, unlike Dr. Caswell, felt that it was safety information which needed to be conveyed to health professionals in 1997. The Australian bulletin had been prepared by the Adverse Drug Reactions Advisory Committee (ADRAC) (Exhibit 122, CBFL-0000125-8). Heading 1. ELECTROLYTE DISTURBANCES WITH ORAL PHOSPHATE BOWEL PREPARATION.
In recent years, the use of oral sodium phosphate solution (Fleet Phospho-Soda Buffered Saline Laxative Mixture) as a bowel preparation for colonoscopy has become more common. Over the past 18 months, ADRAC has received three serious reports, two with fatal outcomes, highlighting severe electrolyte disturbances associated with this oral bowel cleansing solution. The product is available without prescription and can also be used as a laxative at a lower dose…..
Prescribers should be aware that oral sodium phosphate products can cause dehydration (between 1 and 4 L fluid loss), hyperphosphataemia, hypocalcaemia, other electrolyte abnormalities and associated complications. Infants, the elderly, the frail, those with congestive heart failure, and compromised renal function are particularly at risk.
33.) In contrast to the Canadian Safety Information (Exhibit 54), 1997 Australian Bulletin (Exhibit 122), and the FDA's 2001 Science Backgrounder (Exhibit 53), as well as the deposition testimony by Michael Caswell, PhD, about a physiological need for a 12 hour dosing interval, Fleet had already issued an earlier April 1995 Dear Health Care Professional letter (Exhibit 39, 4/5/06) signed by Edward J. Falvo, Category Manager, Laxatives, which encouraged physicians to use a 5 hour administration interval for colon cleansing rather than a 12 hour interval with no information regarding the maximum safe dose.
Safety Profile of 5-h Oral Sodium Phosphate Regimen for Colonoscopy Cleansing: Lack of Clinically Significant Hypocalcemia or Hypovolemia, published in the American Journal of Gastroenterology (Vol. 90, No. 1, 1995), concludes that NaP (Fleet(R) Phospho-soda(R)) is a safe agent in most patients for colonic cleansing, even when given using a 5-hour regimen.
The study's purpose was to carefully monitor hemodynamic and metabolic changes in patients receiving NaP to determine the safety profile is effective using a 5-hour regimen rather than the conventional 12-hour protocol.
The authors concluded that Phospho-soda dosed over 5-hour regimen was (1) well tolerated by patients and did not cause any clinically significant side effects, and (2) is a safe agent in most patients for colonic cleansing.
Since some patients developed asymptomatic intravascular volume contraction and borderline hypocalcemia, the author advised that all outpatients be encouraged to drink fluids liberally and that patients with active medical problems receive appropriate replacement of intravascular fluids. Patients with renal failure, acute myocardial infarction or unstable angina, congestive heart failure, ileus, and gross ascites were excluded because NaP is contraindicated.
Numerous clinical trials (reprints are available) have shown Fleet(R) Phospho- soda(R) to be superior to PEG lavages in efficacy and patient compliance, and to be a safe colon cleansing agent that is priced significantly lower than PEG lavages. Phospho-soda should be the agent of choice for col
onic cl

eansing for your patients….
34.) FDA has repeatedly and publicly expressed its "safety" concerns to Fleet as a result of Fleet's requests to increase dosing from 30-90 mL per 24 hours for colon preparation. In 1996, FDA encouraged Fleet to submit an IND (Investigational New Drug Application) rather than a Citizen's Petition as a better method for obtaining valid human scientific support of the safety and effectiveness of a two 45 mL dose in 10-12 hours for colon preparation. In 1997, in response to FDA's receipt of reports of patient deaths and overdosage, FDA eliminated marketing of the 240 mL container to reduce the potential for consumer confusion. In 1997, FDA denied Fleet's 1993 Citizen's Petition requesting to increase the dose to 90 mL per 24 hours. In September 2001, FDA issued negative publicity in an agency Science Backgrounder, referenced in the Canadian notice, concerning the risks of Fleet Phospho-soda at a dose greater than 45 mL per 24 hours.
35.) In February 2005 Fleet released another letter with the heading: IMPORTANT PRESCRIBING INFORMATION FOR FLEET PHOSPHO-SODA TO THE ATTENTION OF THE United States Health Care Provider. The overall tone of the Fleet message to health care provider once again promotes the benefits of use of Fleet bowel preparation rather than provide users with a notification about risk. Fleet continues to recommend a dosing regimen of two 45 mL doses over 10-12 hours, again the 24 hour dose that does not appear in FDA's tentative monograph. In 2005, there had still been no amendment by FDA of the TFM to include Fleet proposed new dosing regimen. In 2005 FDA had not yet acted on Fleet's June 2003 Citizen's Petition requesting that the new dose with oral phospho-soda be found GRASE.
36.) The Fleet letter, as with the May 2002 letter, references a safety history going back to the 1890's, failing to indicate the product was used for treatment of constipation at much lower dose. The health professional is once again not informed that the history of use of Fleet Phospho-soda as a bowel cleaning product does not extend back to the 1890s. According to FDA's prescription drug medical reviewers, use of Fleet Phospho-soda Oral Solution for bowel cleansing for medical procedures has only recently been developed. Fleet once again implies that Fleet has mandatory reporting of adverse drug events to FDA. The statement "although reporting systems can underreport the number of serious adverse events", fails to inform the health care provider that there is NO required reporting system for an OTC product or OTC pharmaceutical manufacturer in contrast to prescription products. Underreporting is an "understatement". Fleet continues to not mention FDA's September 17, 2001 Science Backgrounder which stated agency concerns about OSPS and dosing ( a total of 45 mL per 24 hours) and also the status of the dosing in the current TFM.
37.) The 2005 letter is inaccurate in that Fleet, in the PDR of 1999 "CONTRAINDICATED" patients with known kidney disease or on sodium restricted diet unless directed by a physician. For all other patient groups which may be at increased risk, the physician was told to "use with caution". The burden for safety and patient selection once again placed only on the physician. However, there had been no sufficiently powered and well designed clinical studies conducted by Fleet to provide accurate dosing and risk information for physicians. In 2005, there also had been no NDA approval for Fleet, despite several filed INDs, able to "confirm the product's safety and efficacy profile" at the dosing being studied by Fleet.
38.) The letter does not inform health care providers that Fleet Phospho-soda was a USP recognized and "grandfathered" drug product not required to demonstrate safety for human use for treatment of constipation. The letter does not inform health professionals that Fleet obtained its new marketing indication for colon preparation from FDA based on assurances to FDA that the active ingredient would continue to remain GRASE for bowel cleansing and suitable for consumer OTC use. The 2005 letter basically reinforces the same safety and effectiveness information provided to health care professionals in the United States in May 2002, namely despite two reports in the medical literature of very rare nephrocalcinosis and transient hyperphosphatemia, overdose, contraindication, user error, Fleet Phospho-soda is "safe and effective". The reader is also informed that Fleet is actively involved with the FDA in order to address the problem. No were is there any information provided to the reader about FDA's tentative final monograph, 2001 Science Backgrounder, product's over-the-counter status, or that adverse event reporting is not mandatory.
The purpose of this letter is to advise you of important new information about adverse events reported in connection with Fleet(R) Phosph-soda(R) and the actions the company is taking to address them, including changes in the prescribing information for use of the product when prescribed as a bowel cleanser.
The use of the product as a bowel cleansing purgative in two 45 mL doses, separated by 10-12 hours, has been extensively studied, confirming the product's safety and efficacy profile. In these studies, the use of Fleet(R) Phospho-soda(R) was shown to provide superior cleansing effectiveness and to result in a greater degree of patient compliance than other types of bowel preparations; and to be a safe, effective, and inexpensive method of bowel preparation. More recently the safety and effectiveness profile of 2 x 30 mL dosing was confirmed in a clinical study sponsored by the company. As a result of this demonstrated safety and effectiveness profile, Fleet(R) Phospho-soda(R) has become the leading bowel purgative and is widely accepted for use by colonoscopists, surgeons, radiologists, and other medical specialists.
Post marketing experience has confirmed the product to be safe and effective. In the 14 years from 1991 through 2004, approximately 44 million doses of 90 mL equivalents of the product were sold in the United States. During that time, there have only been a total of 1 to 5 serious adverse experience reports per million doses sold reported to Fleet to the FDA, or in the published literature in any calendar year. Although reporting systems can underreport the number of serious adverse events that occur, these figures demonstrate that serious adverse events with Fleet(R) Phospho-soda(R) are very rare.

Important New Safety Information

Two papers have been recently published reporting cases of nephrocalcinosis with associated renal failure following administration of Fleet(R) Phospho-soda(R) when prescribed as a bowel cleanser. S. Desmeules, et al., reported in the September 4, 2003 issue of New England Journal of Medicine a case involving a 71 year old woman with no apparent risk factors for nephrocalcinosis who developed non-specific malaise two weeks following use of the product as a bowel cleanser. Her serum creatinine was 4.5mg/dL. Upon renal biopsy, it was hypothesized that ingestion of the product led to obstructive calcium-phosphate crystalluria, followed by intratubual nephrocalcinosis. Her serum creatinine level remained at 1.7 mg/dL one year later.
Markowitz, et. al., reported in the June 2004 issue of Human Pathology on five cases of patients (mean age 69.2) who had normal renal function prior to colonoscopy (mean 0.9 mg/dL creatinine.) and who presented with acute renal failure (mean 4.9 mg/dL creatinine) three days to two months post colonoscopy. Rectal biopsy specimens obtained from each patient revealed diffuse distal tubular injury and deposition of calcium phosphate. They concluded that "…acute nephrocalcinosis is a seemingly rare complication of bowel cleansing with OSPS" and that the pathophysiology "likely involves transient hyperphosphatemia, volume depletion exacerbated by concurrent ACE-I, ARB and diuretic use; and elevated distal tubular phosphate and calcium concentrations." All five of the subjects were hypertensive — four were on ACE-I (angiotensin-converting enzyme inhibitor) or an ARB (angiotensin receptor blocker) and two were on diuretics. It is important to note that one case involved an overdose as well as bowel obstruction, a contraindication to use of the product, and the authors indicated another involved use in a patient in whom the OSPS is otherwise contraindicated.
In addition, the company has very recently received thirteen additional reports of acute renal failure in patients who use OSPS. These reports span a period of over eighteen months. At present, the company has very limited information as to how the product was used in these cases, how much was taken and when, whether the patients had contraindicated conditions and what the outcomes were. The company is attempting to obtain additional information for each of these reports. It is important to note that none of these cases involved death. Based on the very limited information obtained to date, some of these cases appear to have included patients who overdose; patients in whom its use may not have been appropriate; patients at risk for dehydration, such as elderly and /or debilitated patients; patients on ACE-I/ARB's; and patients taking drugs such as diuretics that can cause dehydration.

What C.B Fleet is Doing in Response to this Information

Revised Packaging and Professional Labeling
In response to the initial reports of these cases, the company, after meeting with the U.S. Food and Drug Administration ("FDA"), revised the professional labeling for Fleet(R) Phospho-soda(R) to emphasize the importance of adequate hydration when prescribing the use of the product at bowel cleansing dosages. To reiterate and reemphasize this information the company is revising the labeling on the packaging sold at retail and again revising the professional labeling for the product made available to health care professionals.
The retail packaging of the product is being revised to state the dosing in tablespoons and to specify the number of tablespoons in each bottle. In addition, to reemphasize the need for adequate hydration when using the product, further detail is being provided as to amount of clear liquids that should be consumed when using the product. A statement that the product is in a multidose container and that "Overdosage Can Be Harmful" is being added to the flap of the 90 mL (3 fl. oz.) container. This is in addition to the current statement on the front Panel that the product is in a multidose container and the current warning that taking more than the recommended dose can be harmful. Lastly, dosing for laxative use and use as a bowel cleanser in medical procedures is being separated…. Additional Studies
The company has also undertaken, with input from the FDA, a number of animal and human clinical studies to investigate these findings… (citations omitted)
39.) FDA approved a New Drug Application (NDA) NDA 21-097, not for Fleet, but for new drug sponsor InKine Pharmaceutical Co. Inc. ("InKine") to begin its marketing of prescription Sodium Phosphate Tablet, VISICOL(R), at a dose of 60 gm (90 mL of Oral Phospho-soda Solution) intended for cleansing of the bowel as a preparation for certain procedures. VISICOL is a tablet form of 1.5 gms of sodium phosphate/sodium biphosphate. VISICOL is marketed as a prescription drug with prescription labeling (21 CFR 201). Prescription manufacturers have mandatory adverse event reporting and FDA has authority for facility inspections. Due to patient safety concerns, despite a long marketing history of Fleet Phospho-soda USP as a laxative and later marketing for colon preparation, FDA's Office of New Drug Evaluation, Division of Gastrointestinal and Coagulation Drug Products, medical officer required NDA sponsor InKine to address safety by increasing the safety monitoring of all subjects enrolled in the VISICOL IND clinical trials.
40.) As of June 2006, the FDA's TFM for the nonprescription OTC drug product still contains a maximum dose of 45 mL per 24 hours as a generally recognized as safe and effective (GRASE) and not misbranded. As of 2006, FDA has not issued its Final Monograph for Oral Laxative Sodium Phosphate Oral Solution and has taken no steps to change the maximum "GRASE" dose. For over 30 years, the FDA's OTC monograph process for Fleet has not been brought to final closure. With the monograph not yet finalized, FDA and the limited number of members of the Office of Nonprescription Drugs have remained reticent to take on official regulatory action against laxative OTC manufacturers. (FDA's Sec. 450300 OTC Drugs- General Provision and Administrative Procedures for Marketing Combination Products (*OTC drug products containing combinations of ingredients)(CPG 7132b.16):
In general, prior to final publication of a proposed monograph it is not appropriate to pursue regulatory action unless directed by headquarters.
(Note: In 2006, the management of the Office of Nonprescription Drugs includes a physician director, pharmacist associate director, a regulatory counsel, policy analyst, social science analyst with 5 support personnel. In terms of product review, there are 6 medical officers, 7 project managers and 4 review teams. CDER's Office of Nonprescription Drugs has a total of 37 staff members in 2006. In way of comparison, the Office of New Drugs for review of new "prescription drugs" has a total staff of approximately 1,000.) Once the FM is published, regulatory action against a firm violating the conditions of the FM will occur at the discretion not of the Office of Nonprescription Drugs but rather CDER's Office of Regulatory Affairs. Any future regulatory action after publication of the FDA will be based on ORA's evaluation of potential public health risk and the Agency's current enforcement action priorities.
41.) Despite not having published a finalized monograph, based on public safety concerns, FDA's Office of Nonprescription Drugs has opted to take certain regulatory actions available to it to help reduce the immediate risk to public health posed by Fleet Phospho-soda used for colon preparation. Throughout the monograph process period, Fleet, sponsor of an OTC product, has remained the entity responsible for ensuring its own conduct and compliance with applicable sections of the Federal Food Drug and Cosmetic Act, the safety of its product, adequacy of labeling and public safety.
42.) As of June 2006, FDA has not yet responded to a 2003 Fleet Citizen's Petition requesting to amend the TFM with a range of higher OTC doses- two 30mL (60 mL) or two 45 mL (90 mL) sequential doses at 10-12 hours. This was the same higher dosing range included in Dr. Kanapka's September 5, 2002 email (Exhibit 40), in the Fleet ACCU PREP Kit marketed since 2003, in INDs and Citizen's Petitions submitted to FDA for support of safety and efficacy for a new 24 dosing for colonic preparation, but not recommended by Fleet prior to 2006.
43.) As will be discussed further, the OTC process was not designed by Congress to be remove unsafe grandfathered products from the market, particularly for a USP product, which had already passed OTC Panel review. For OTC products and firms making OTC products, Congress reduced the regulatory oversight of FDA based on a marketing history with support that a product was GRASE. OTC pharmaceutical firms, unlike prescription drug manufacturers, do not have mandatory adverse event reporting requirements. FDA was not given authority to inspect OTC facilities and records until the Food & Drug Administration Modernization Act of 1997. Manufacturers of OTC drug products have reduced required interactions with FDA.
44.) Sodium Phosphate Oral Solution, USP, or Fleet Phospo-Soda was "grandfathered" as "safe" for treatment of constipation as a laxative. Its product formula is recognized by the USP as an oral laxative. Fleet Phospho-soda has been on the United States market as an oral laxative for relief of constipation since 1893. Its marketing in the United States as an oral laxative began before the passage of the 1938 Federal Food, Drug and Cosmetic Act. There has been no product testing or formal clinical trials required for Fleet Phospho-soda to begin marketing in the United States market as an oral laxative, it was grandfathered or deemed to be a safe human drug product ingredient. Roughly around the time of the FDA's initiation of an OTC review and monograph process to begin to retrospectively review drugs previously grandfathered as safe, Fleet requested that FDA allow it to add a new indication, bowel preparation for colonoscopy, x-ray imaging or surgery, to Fleet Phospho-soda oral laxative indication. FDA, without review of supporting human data from randomized control clinical trials or a New Drug Application, based on a history of the product's safe oral use as a laxative, accepted Fleet's assurances that a new claim for bowel cleansing for procedures would be a suitable OTC claim for Fleet Phospho-soda. It is the use of Fleet Phospho-soda for its "new" OTC claim, namely bowel cleansing for procedures, which compelled Fleet to begin to alter laxative administration dosage and has been associated with patient injuries and deaths.
45.) In contrast to its handling of Fleet, FDA did not allow
drug sponsor I

nKine the ability to market Sodium Phosphate, USP, in a tablet form, as an OTC drug intended for colon preparation. FDA required InKine to obtain pre-market approval of a New Drug Application (NDA), supplying clinical data to support safety and efficacy as a colon preparation. Unlike Fleet, InKine was required to submit an IND per the requirements of 21 CFR 312 and obtain approval of a completed NDA per 21 CFR 314. The VISICOL NDA, NDA 21-097, was required to support efficacy for prescription drug, VISICOL at a 60 g (90 mL) dose in 24 hours for bowel cleansing. FDA did not require InKine to do additional basic animal pre-clinical safety testing for Sodium Phosphate, USP due to the active ingredient's long history as a safe oral medication and grandfathered drug. FDA allowed InKine to rely on animal studies already in the medical literature per the Least Burdensome Method to support safety.
46.) In 2001, VISICOL began commercial marketing as a prescription drug intended for bowel cleansing for procedures, and unlike Fleet Phospho-soda, it was marketed with prescription labeling. The safety information included in the initial VISICOL label reflected issues, which should have also been known to Fleet, that occurred during the clinical trials and the medical literature for similar products used for bowel cleansing. One safety issue addressed by VISICOL in its product insert and labeling, which has never been addressed by Fleet in its OTC label or professional label in the PDR, despite reports occurring in the medical literature, is an association between phospho-soda use with production of apthous ulceration within the colonic gastrointestinal tract. The ulcerations have been reported to occur in patients using either oral or enema sodium phosphates for bowel preparation.
47.) The problem with the presence of ulcers with Fleet oral or enema Phospho-soda or VISICOL Tablets is that colonic mucosal ulcerations seen at time of colonoscopy can be incorrectly misinterpreted as inflammatory bowel disease, a false diagnosis that will carry significant consequences for the patient. VISICOL's prescription label has the following Warning statement:
Administration of VISICOL Tablets may induce colonic mucosal apthous ulcerations, an endoscopic finding observed with other sodium phosphate cathartic preparations. This colonoscopic finding should be considered in patients with known or suspected inflammatory bowel disease.
48.) The VISICOL prescription labeling also provides the following WARNING information to the physician users.
WARNINGS
Administration of other sodium phosphate-containing products, such as enemas or non-prescription liquid purgatives, has resulted in fatalities due to significant fluid shifts, severe electrolyte abnormalities, and cardiac arrhythmia. These have been observed in patients with renal insufficiency or bowel perforation, and with misuse or overdose of these products.
Use with caution in patients with impaired renal function, pre-existing electrolyte disturbances (such as dehydration or those secondary to the use of diuretics), or people taking drugs that may affect electrolyte levels. Patients with electrolyte abnormalities such as hypernatremia, hyperphosphatemia, hypokalemia, or hypocalcemia should have them corrected before treatment with VISICOL(R) Tablets…
Prolongation of the QT interval has been observed in some patients who were dosed with VISICOL(R) Tablets. QT prolongation with VISICOL(R) Tablets has been associated with electrolyte imbalances, such as hypokalemia and hypocalcemia. VISICOL(R)Tablets should be used with caution in patients who are taking medications known to prolong QT interval, since serious complications may occur.
There have been reports of generalized tonic-clonic seizures and /or loss of consciousness associated with VISICOL(R) used in patients with no prior history of seizures. Cases of seizure were associated with electrolyte abnormalities (e.g.hyponatremia, hypokalemia, hypochloremia, hypocalcemia, hypomagnesia) and low serum osmolality. Neurologic abnormalities resolved with correction of fluid and electrolyte abnormalities. Other purgatives including sodium phosphates solution and PEG-3350 containing products, have also been associated with seizures and alterations of consciousness in patients with or without a prior history of seizures. VISICOL(R) should be used with caution in patients with risk factors for hyponatremia, e.g. SIADH, a history of electrolyte abnormalities, inadequately treated hypothyroidism, use of other drugs associated with hyponatremia, e.g. thiazide diuretics or adrenal insufficiency, or with risk factors for development of tonic-clonic seizures,
50.) March 16, 2006, FDA approved for sponsor Salix, NDA N021892, to market prescription OsmoPrep as intended for bowel cleansing for procedures.
OsmoPrep, like VISICOL, is a prescription drug. OsmoPrep is a tablet bowel preparation containing sodium phosphate monobasic monohydrate and sodium phosphate dibasic anhydrous. However, the OsmoPrep tablet bowel preparation contains a reduced amount, of sodium phosphate, 48 gms, than either the use of the highest dose of ACCU PREP or VISICOL.

OPINION #2

51.) Any United States company, whether marketing a drug, device, biologics, cosmetic, or food is prohibited by its responsibilities under the Federal Food, Drug and Cosmetic Act (FDCA) from selling in the United States an FDA-regulated product that is not safe and effective for its intended use or that is adulterated or misbranded. FDA-regulated products, whether foods, cosmetics, drugs, devices or biologics, animal products are required to have adequate labeling which provides instructions for use and adequate warnings. Pre-1962 OTC drugs still on the market are generally recognized as safe and effective (GRASE),and have limited FDA oversight. OTC drug manufacturers are primarily self-regulated in terms of oversight of labeling and warnings and adherence to FDA's published monographs. Fleet has persisted in marketing an OTC drug to consumers and health care providers (HCP) as intended for bowel preparation for which a Final Monograph has not yet been issued by FDA, with inadequate instructions and warnings. Fleet has been able to market Fleet Phospho-soda intended for OTC colon preparation via a unique favorable regulatory set of circumstances. Fleet's conduct with United States health care providers and consumers has shown a disregard for its responsibility to protect patients and to ensure its own compliance with the Federal Food Drug and Cosmetic Act. Fleet has not provided adequate warnings to physicians and patients about the risks of Fleet Phospho-soda while it has attempted to gain the colonoscopy preparation marketshare as an OTC product.
52.) From the documentation reviewed, prior to recommending the use of a new dosage of an active ingredient for OTC colon preparation, Fleet did not perform adequate testing designed to address safety of a new proposed indication, appropriate therapeutic dose range, timing, hydration regimen and subpopulations at increased risk. CB Fleet's actions for failing to monitor product safety and update product labeling regarding bowel preparation directly contributed to the kidney injuries of Mr. Timothy Bracey following colonoscopy and laparoscopic colostomy reversal June 13 and June 21, 2004.
53.) Fleet has instituted a complex muli-tiered marketing strategy for promoting its OTC product to physicians for use for colonic preparation that includes OTC Professional Labeling placed in the PDR but which fails to provide adequate warnings and instructions for use. It has not provided either physicians or consumers with adequate discussion of the potential risks which have been associated with its product worldwide when used for colon preparation. As a result, physicians and consumer have not received full disclosure of information that would allow them to make an informed determination regarding risk versus benefit for use of Fleet Phospho-soda for bowel cleansing, particularly in patients older than 50 years of age. Unlike either the consumer or the health care provider, Fleet has been made aware that its labeling and promotions have not been consistent with the FDA's TFM for a product GRASE.
54.) As an OTC manufacturer, and particularly until the publication of the Final Monograph, Fleet remains "responsible" for monitoring its own conduct under the Act, the adequacy of its product labeling and promotions to physicians and patients and for ensuring its compliance with current Good Manufacturing Practices (cGMP) and protection of patients. Fleet's Professional information, other than being placed in the Physician Desk Reference(R), a document which contains prescription drug information, is "not" prescription labeling. Unlike prescription drug labeling, Fleet's information in the PDR has not been required to be reviewed or approved by FDA as part of the NDA process. There are no FDA drug regulations that pertain specifically to the format and contents of "professional labeling" for an OTC product or labeling for an OTC product intended for distribution in vehicles such as the PDR.
55.) The general drug labeling regulations under the Act regarding adequacy of warnings and instructions for use and misbranding are applicable to drug products including OTC products. Fleet's PDR professional labeling was not updated to provide physicians with a medical literature reference regarding the association of nephrocalcinosis and chronic renal failure with patients using Fleet Phospho-Soda.
56.) Up through the Fleet 2006 PDR, professional label does not include information for physicians regarding findings seen in animal studies such as Dr. Moeckel's rat study conducted for Fleet. Dr. Moeckel's rat study showed an association of elevated oral phosphate, diabetes, angiotensin converting enzyme-Inhibitor (ACE-I) and dehydration with production of renal failure and Acute Tubular Necrosis (ATN). The rat study also showed that increased oral phosphate, diabetes and ACE-I were conditions associated with hyperkalemia with or without the presence of dehydration. The May 2006 recommendation from the FDA regarding acute phosphate nephropathy, renal failure and oral sodium phosphate bowel cleansing products was that OSP should be used with caution in patients taking diuretics, ACE inhibitors, angiotensin receptor blockers (ARBs) and NSAIDS.
57.) The professional label in the PDR does not inform physicians that "soft tissue calcification" could occur at the serum calcium and serum phosphate levels produced by the administration of a second 45 mL dose within 24 hours. The professional label does not include several animal studies concerning phosphate-induced nephrocalcinosis, including a 1981 dog study by Schneider P, Ober KM, and Ueberberg H, Contribution to the phosphate-induced nephropathy in the dog. Comparative light and electron microscopic investigations on the proximal tubule after oral application of K2HPO4, Na2HPO4, KCl, and NaCl. Exp Pathol 1981; 19:53-65.
58.) Despite the Fleet Phosph-soda product having been on the market since 1893, it has not been marketed for colon preparation since 1893. Colon preparation is a relatively new indication for this product. Fleet does not appear to have conducted sufficiently powered "safety" studies designed to address the safety of bowel cleansing for health care providers and patients. (Fleet Phospho-soda Safety Studies, Plaintiff's Exhibit 90, 5/9/06, a listing of 28 "safety" studies.) Fleet has conducted small underpowered efficacy (marketing) studies designed primarily to focus on support of the performance data of the sue of a Phospho-coated sodium phosphate powder for bowel preparation. There is no evidence that Fleet's IND has successfully obtained FDA's approval as safe and effective for the proposed new OTC indication and dosing regimen. The IND was submitted not to Nonprescription Drugs (OTC) but to prescription drugs (Rx) and the Division of Gastro-intestinal and Coagulation Drug Products. Unlike nonprescription or OTC drugs, an IND (*per 21 CFR 312) is to have review and monitoring by FDA's prescription drug review staff. The individual at Fleet responsible for signing FDA's cover letter and responsible for the contents of the 2004 IND Annual Report at Fleet was Samuel Bohannon, Domestic Regulatory Affairs Manager. Joseph Kanapa, Ph.D., Director of Product Safety, was the individual identified by Fleet as responsible for the review and evaluation of the information relevant to the safety of the drug. The individual responsible for monitoring the conduct and progress of the clinical trial, with a transfer of sponsor obligations to the contract research organization (CRO), was Michael Adams, Pharm. D. SFBC, New Drug Services. The Annual Report for IND 57,445, was for a single-randomized, single blind, parallel group evaluation covered the reporting period December 15, 2002, through December 14, 2003 filed to provide additional information to the FDA per 21 CFR 312.23(a)(10). The Investigators Brochure report had similar types of information and included the recording of rehydration information si
nce patient hy

dration was viewed as an essential role in preventing "toxicity". During that annual reporting period, Study F02.090 was initiated. FDA was also provided a new Investigator's Brochure, release data March 19, 2003. The brochure included information for studies F00.020, F00.040, F02.030, and PS-9902. As stated, it does not appear that as of 2007 FDA has accepted the IND as valid support of safety and effectiveness as an OTC for the dosing regimen and new indication.
69.) CBFL2-0001497-576 is a document identified as an IND Submission, with a fax cover sheet to Dr. Thomas Garvey, III, MD, Garvey Associates, Inc., from Sarah Post, Fleet Company, Inc. dated 8/18/98. It is labeled Item 3- Introductory Statement [21CFR 312.23(a)(3)]. Phospho-soda Solution Sodium Phosphates Oral Solution USP 20 and 45 mL and Coated Phospho-soda Powder 30 mg. Under Broad Objectives is the following information about the purpose of the IND:
In the Federal Register of May 21, 1998 (Vol. 63, No. 98:27836-278930) the Food and Drug Administration, Department of Health and Human Services published a "Final Rule" (21 CFR Part 201) which established the "Package Size Limitation for Sodium Phosphates Oral Solution and Warning and Direction Statements for Oral and Rectal Sodium Phosphates for Over-the-Counter Laxative Use.
The Final Rule limits the use of Sodium Phosphates Oral Solution for Over-the-Counter Use to a single dose of 45-mL within a twenty-four (24) hour period and is further requiring a "Warning" statement to that effect on the Label.
The purpose of this IND is to demonstrate the Safety and Efficacy of the use of two 45-mL Phospho-soda oral solution when administered twice daily within a twelve (12) hour period. The Safety data that will be gathered under the "Retrospective Clinical Protocol" will be used to support Professional Labeling.
In addition, Fleet Co. Inc intends to undertake clinical trials to support the Safety and Efficacy of a 30-mL dosage form of Phospho-soda (for OTC use) when administered twice daily over a 12 hour interval e.g. initial 30-mL administered 7 PM the evening prior and 30-mL administered at 6 AM just prior undergoing colonoscopy.
70.) Under the IND process, 21 CFR 312, the sponsor is required by the Act and regulations to provide all known human performance experience and animal testing for a drug from both foreign and USA sources, published and unpublished which may have an impact on safety and efficacy. The sponsor is also required to periodically update the IND with all available safety and performance information and provide adverse event reporting. There is a November 19, 1998 Item 9- Previous Human Experience (21 CFR 312.23 (a)(CBFL2-0002526, Phospho-soda Solution Sodium Phosphates Oral Solution, Sodium Phosphatase Oral Solution USP, 30 and 45 mL. Section 9.4 Overall Summary and Conclusions, (CBFL 2- 000251), unlike the information being provided to United States physicians in its PDR professional labeling, and beginning as early as 1998 IND submission for a new powder form of Fleet Phospho-Soda, has Fleet stating that:
Preliminary results from pilot studies conducted by Fleet suggest that a dose of 2 x 30 mL may be as effective as 2 x 45 mL. If this is true, the lower dosage, by virtue of a 33% reduction in sodium and phosphate load, should further improve the safety margin. Preliminary evidence tends to support a dose-related decrease in serum electrolyte changes. This is one of the questions this IND is intended to address.
Serious adverse experiences have been associated with the use of oral sodium phosphate and other bowel preparations. These events appear to be rare and have not been reported at rates that suggest a negative benefit-to-risk. The vast majority have been associated with medically-prescribed or accidental overdoses. Problems which have occurred in patients receiving doses at or below 2 x 45 mL in 24 hours have been associated with elderly or debilitated patients who have had predisposing factors. Adequate hydration would appear to have an essential role in preventing toxicity.
At any given dosage level, the magnitude of electrolyte and intravascular volume changes are expected to be worsened by pre-existing renal insufficiency, dehydration, electrolyte abnormalities, colonic dysfunction or intestinal obstruction. As a result, oral sodium phosphates in the doses recommended for bowel preparation should be used with caution, or contraindicated, in debilitated patients, patients who are dehydrated or who are fluid-restricted, patients with renal insufficiency, patients who may be unable to tolerate relatively rapid decreases in intravascular volume (e.g., patients with ascites, congestive heart failure, myocardial ischemia, or cerebrovascular insufficiency), patients with colonic dysfunction (e.g., ileus) or intestinal obstruction. Furthermore, patients must be instructed to maintain adequate hydration, by drinking clear liquids, during bowel preparation. Caution should be exercised in patients with impaired mental status to assure that they (or a care giver) can understand and follow directions for correct dosage and hydration.
71.) In Fleet's February 11, 2004 IND No. 57,445 IND Annual Report, there was the following laboratory evaluation safety information for 48 patients (CBFL2- 0000547):
5.2.2.4.2 Clinical Laboratory Evaluations
The most prevalent serum electrolyte result outside the normal limits at the end of the study was phosphorous. Forty-seven (47) patients had higher end-of-study results. The reference range for this parameter was 2.5-4.5 mg/dL. The results at the end of the study ranged from 4.6-8.3 mg/dL.
72.) There is no evidence that the Fleet INDs have successfully demonstrate to FDA the safety and efficacy of administering two 45 mL or 30 mL doses over a twelve hour period for bowel cleansing as either a prescription or OTC product.

III. UNDERLYING FACTS AND DATA IN SUPPORT OF OPINIONS

73.) See Attached List of documents provided to me for my review.

A. Summary of the OTC Regulatory History of OTC Oral Laxative Oral Sodium Phosphates

74.) The OTC use of Fleet Phospho-Soda for bowel preparation has been under consideration by the FDA since 1975 with a proposed Tentative Final Monograph (TFM) in 1985 (50FR 2124) proposed for all OTC Oral Laxative drug products including Phospho-Sodium Oral Solution. Currently only a Tentative Final Monograph (TFM) and a September 17, 2001 FDA Science Backgrounder have been released by the FDA indicating a total dose of no more than 45 mL in a 24-hour period is generally recognized as safe and effective (GRASE) and not misbranded. If the Final Monograph (FM) was in place and Fleet did something outside the monograph, then FDA would take regulatory action "if" it considered it in the public interest. However, to take such an action after the release of the FM would depend on FDA's Office of Regulatory Affair's decision which would be based on the public interest, and not CDER's Office of Nonprescription Drug staff.
75.) On a number of occasions, FDA has reopened the proposed rule for the final monograph to discuss new data or information. On March 31, 1994, (59 FR 15139) FDA made an amendment to the TFM to limit the OTC drug container size for Sodium Phosphates Oral Solution to not greater than 90 mL (3 ounces) and to add a warning; on May 21, 1998 (63 FR 27886) a TFM amendment was made to expand additional General and Professional labeling for oral and rectal sodium phosphates drug products; but on December 9, 1998 (63 FR 67817) FDA issued a Notice of Withdrawal of proposed TFM amendment of May 21, 1998 to expand professional labeling for oral and rectal sodium phosphate drug products and indicated an intent to re-propose at a later time; on October 22, 2003 FDA reopened the comment period for the OTC Oral Laxative rule. On August 22, 1997 FDA had officially denied Fleet's June 25, 2003 Citizen's Petition to amend the agency's Final Monograph to indicate a new dosing regimen for colonoscopy preparation of two 45 mL doses of sodium phosphates oral solution taken at 10 to 12 hours apart as a bowel cleansing system. After FDA's denial of the Fleet 1993 Citizen's Petition for the new dose, on June 27, 2003 Fleet submitted a Citizen's Petition to amend the Final Monograph now to include an oral dosing regimen for bowel preparation of two
78). A prescription drug product is typically a product which has been approved by FDA through a New Drug Application (NDA) for marketing as safe and effective with prescription labeling to be used by a trained and licensed health care providers. The product requires that the consumer first obtain a written prescription and interact with a health care provider. There are a certain number of grandfathered prescription drugs which may not have required FDA's approval of a NDA, however, they have been required to adhere to the requirements of prescription labeling, Good Manufacturing Practices (GMP), mandatory adverse event reporting and FDA inspection of facilities and records.
79.) A competitor prescription bowel cleaning product to Fleet Phospho-soda Solution, VISICOL Tablets (sodium phosphate monobasic, USP, sodium phosphate dibasic anhydrous, USP) was approved by FDA by an NDA in September 9, 2000 (NDA 21-097). VISICOL was approved as intended for cleansing the bowel for preparation for colonoscopy for InKine Pharmaceutical Company, and is available only as a prescription product. Two doses of 30 gms (40 tablets) of VISICOL are taken twelve hours apart to induce diarrhea. Each administration is to have a purgative effect for 1 to 3 hours. The VISICOL NDA information included a clinical study of 957 adult patients comparing the performance for colonoscopy preparation of VISICOL to NuLYTELY, a commercially available polyethylene glycol-salt (PEG-salt) solution also available by prescription and approved by NDA for Braintree Laboratories. Safety for the use of sodium phosphates in a tablet format in the NDA was predicated on a long history of use of oral phosphates solution use as a laxative, a product that had been on the market as a laxative prior to the passage of the 1938 Food, Drug and Cosmetics Act.
80.) Despite the history of long safety and grandfathering of the product as "safe", the FDA prescription drug evaluation division required the sponsor of the NDA do perform additional safety monitoring of patients in the clinical trials. (VISICOL NDA discussed further below).
81.) Prescription labeling is intended to be read and understood by a trained health care provider and not a lay consumer. Each State determines the level of training required for a health care practitioner to be able to write prescriptions in that State. FDA has not been given legal authority to determine who is able to write prescriptions in a State. Certain prescription drugs also require that information intended for use by a layperson accompanies the product, for example birth control pills and estrogen products have consumer information. Consumer information is usually required when, due to safety concerns, the patient should be able to take home reminder information after leaving the health care provider.
82.) Prescription labeling is used when labeling cannot be written for use of a drug intended for a nonprofessional that can ensure safe and efficacious use of the drug. The average layperson should not be expected to be able to make clinical diagnoses of conditions which may limit or change the use of an OTC product. The Drug Enforcement Bureau (DEA) regulates the prescribing of certain controlled drugs with established abuse potential.
83.) Prescription drug labeling has been available since an amendment to the Federal Food and Drug Act in 1951. The Durham-Humphrey Amendment defined the kinds of drugs that could not be safely used without medical supervision and restricted the sale of these drugs to prescription by a licensed health care provider. (21 USC 503(b)).
84.) In contrast, OTC labeling, whether for drug or device, is labeling designed and intended to be understood by a "layperson" to be able to use a product safely and effectively. Fleet is an example of an OTC pharmaceutical firm that makes and markets OTC products. As an OTC pharmaceutical firm it is not subject to the same FDA regulatory oversight as a manufacturer of prescription pharmaceuticals.
85.) The OTC drug review process was established by FDA to facilitate evaluation of "generally" recognized safe and effective drug products which had been marketed in the United States prior to May 11, 1972. These products were not required to have been scientifically demonstrated to be safe and effective, the requirements for prescription drugs. Many OTC drugs, including Fleet's Phospho-Soda products are members of "old" therapeutic products which have never been required to obtain FDA's marketing approval or undergo a review for United States marketing. Fleet's Phospho-Soda as an old drug, and phospho-soda as an old active ingredient were not required to be approved as safe and/or effective by FDA and are deemed by statute (grandfathered) to be "safe" because on the United States market prior to the Food, Drug and Cosmetic Act of 1938 for that same indication and never shown to be "not safe".
86.) The physical container of the oral solution is a container allowed by the USP. (USP described further below). A bottle of Fleet's Phospho-Soda Oral Solution is a clear plastic container with markings imprinted with clear raised letters. There is product name Fleet Phospho-Soda Oral Saline Solution: "For the relief of occasional constipation and bowel cleansing", 1.5fl oz (45 mL) or 3 fl oz (90 mL). On the other surface, again only as raised clear letters is the following: See primary packaging for instructions and warnings, Read carefully before each use. Each 5 mL contains: Active ingredients: Monobasic sodium phosphate 2.4g and dibasic sodium phosphate 0.9g. Fleet Co, Inc. Lynchburg, VA 24502 USA. The only "visible" printing on the clear bottle is a bla
ck stamp of th

e 0501722 (lot or batch number) and EXP XX XX (expiration date.) The bottle is devoid of measurement indicators and requires fairly good eyesight to be able to identify that there is any form of information on the bottle other than the expiration date. This would not be user friendly labeling for elderly patients or a patient with reduced eyesight. The design of the packaging implies that the entire bottle is to be used.
87.) Fleet Phospho-Soda was eventually legally required to support "efficacy" as an OTC Oral Laxative drug active ingredient after the passage of the Kefauver-Harris Amendment of 1962 to the Act. The amendment followed on the wake of public concern regarding the drug thalidomide. The amendment required that all FDA regulated drugs on the market as safe be shown to be "efficacious" for a specific intended use. If no "efficacy" for an indication could be supported to the Panel, the product was to be removed from the market by FDA. FDA was to retrospectively review the efficacy of nearly 4,000 prescription drugs introduced onto the US market from 1938 through 1962. FDA selected approximately 420 drugs that were considered as low risk for consideration for OTC classification. For the large task, the FDA responded by seeking external advice from the National Academy of Sciences-National Research Council (NAS- NRC) ("the Panel") on previously marketed prescription drugs, established a review process for active ingredients being considered for use as OTC drug ingredients, and extended such committee review to include new prescription drugs. The FDA's retrospective drug efficacy review program was called "Drug Efficacy Study Implementation (DESI)" Review.
88.) In the years following 1962, literally thousands of prescription drug items, as well as OTC drug products, were removed from the US market by FDA due to a lack of support for efficacy for any indication. FDA also required manufacturers to update their product labeling to reflect known medical facts regarding drug safety and efficacy and to come into compliance with FDA's proposed changes in drug labeling requirements. This amendment to the FDCA also contained a "grandfather" clause which provided that drugs commercially marketed available in the US after June 25, 1938 and prior to October 9, 1962 and which had not yet been approved as new drugs and were not considered "new" drugs by FDA should not be considered "new" drugs under the amendment, provided the products had not significantly changed labeling or formulation. These "not new" drug products were specifically exempted from demonstration of efficacy requirements of the amended Act.
89.) Unrestricted increased access by the public to certain prescription drugs approved under NDA would eventually occur through FDA's allowing a switch from prescription to OTC drugs (RX to OTC switch). Such a mechanism for enhanced access by the public of certain new prescription drugs, approved by NDA, and made OTC was strongly encouraged by the insurance industry that wanted relief from reimbursement for the cost of prescription drugs and a health system with greater emphasis on patient self-care.
90.) Fleet Phospho-soda, which had been sold in the United States as a laxative since the 1890s, at no time was required to obtain FDA's approval of a marketing application as a "new" drug. It was not required to demonstrate safety as a human drug, and has not been a prescription drug, unlike its current competitor products for bowel preparation.
91.) After 1972, the official OTC drug process at CDER became a three-phase public rulemaking process with each phase requiring an official Federal Register publication which results ultimately in the establishment of standards (*monographs) for an OTC therapeutic drug category. There are more than 80 classes (therapeutic categories) of OTC drugs, ranging from acne drugs, cough/cold/decongestant drugs, to weight control drugs. FDA is to "generally" oversee OTC drugs to ensure that they are properly labeled and that the benefits of the drug outweigh the risks. However, the involvement of FDA with OTC product active ingredients, due to the perceived safety and low risk to the public, has been significantly reduced from prescription and new drugs, biologics and medical device oversight. Manufacturers of OTC drugs have been "exempted" from certain requirements which would involve FDA's oversight and interaction with the manufacturer.
92.) Because of the initial OTC drug products' history of marketing in the United States, manufacturers of OTC drugs, unlike OTC devices and prescription and generic drug manufacturers, are not legally required to file adverse event reports with FDA. The true number of adverse event reports occurring with OTC drugs is unknown by FDA and cannot be estimated. OTC drugs are also less likely to be associated with an unexpected or negative outcome by physicians and the public due to an "OTC perceived low risk". Therefore, the filing of adverse drug experience reports for OTC products is voluntary and the actual under-reporting of the OTC industry is unknown by the FDA. However, health risks do occur with OTC drugs. For example, FDA for years was unable to estimate the true lack of adverse event reporting for the OTC cough and cold medicine involving phenylpropanolamine (PPA), also a pre-1938 grandfathered "safe" drug, which helped contribute to the significant delay in removal of PPA from the United States OTC market despite Agency "safety" concerns. Therefore, FDA's receipt of adverse drug experience reports for OTC products and prescription drugs or NDA to OTC switch cannot be compared in a meaningful manner since the requirements for reporting are different and physician and consumer level of risk of suspicion for OTC products is different. Prescription drugs are viewed by the public as potentially more risky than OTC products.
93.) FDA, until passage of the Food, Drug and Modernization Act ("FDAMA") of 1997, was not given authority by the Act to have access to OTC manufacturing facilities and product records for inspection. Without mandatory adverse drug experience reporting FDA is reliant on OTC firms to have accurate safety information and complaint handling procedures when inspected. FDA must rely on the OTC pharmaceutical firm to ensure its own compliance with the Act and current Good Manufacturing Practices such as complaint handling, failure investigations, corrective and preventive actions (CAPA), and labeling changes. Since most OTC products have been marketed for years, physician and patients simply "assume" that an OTC product is safe. Therefore, the level of suspicion by consumers about an OTC drug's involvement in an adverse event is low for both health care providers and patients.
94.) As FDA wrote in the 1985 (50 FR 2124) notice of proposed rulemaking for tentative final monograph (TFM) for OTC Oral Laxatives drug products regarding the marketing of OTC procedures, the OTC review procedures did not preclude the Panel from making recommendations about OTC drug advertising (B. General Comments on Laxatives, Response 10). The Federal Trade Commission (FTC) has the primary responsibility for regulating OTC drug advertising. FDA retains authority to regulate OTC drug advertising that constitutes labeling under the Federal Food, Drug and Cosmetic Act. Under the Act, a manufacturer can be prohibited from advertising a drug to treat a condition for which there are no adequate instructions for use on the label. In addition, for an OTC drug to be generally recognized as safe and effective (GRASE) and not misbranded, the advertising of the drug must satisfy the FDA regulations at 21 CFR 330. l(d), which states that the advertising may prescribe, recommend, or suggest the drug's use only under the conditions stated in the labeling.
95.) FDA has been continuously evaluating ingredients and labeling of OTC dru
gs as par

t of "The OTC Drug Review Program". FDA's final goal is to establish OTC drug Final Monographs for each therapeutic class category. Manufacturers of OTC products are required to be manufactured in compliance with cGMP (21 CFR 211). Essentially two post FDCA 1938 regulatory pathways exist for an OTC sponsor to begin legal marketing of an OTC drug: 1) support of compliance with the minimum requirements of the OTC drug monograph and without any further requirement for FDA premarketing review; for example Fleet Phospho-soda; or 2) support the start of marketing under an approved NDA or ANDA and request an OTC switch, for example Tavist-D.
96.) The OTC regulations do not specifically address the mechanism that FDA will use to remove an OTC drugs from the market based on issues of safety. For example, FDA was engaged with the OTC industry for years in order to support a "safety problem" with grandfathered safe phenyl propanolamine (PPA) in order to help to compel removal from both OTC and prescription products. (*OTC and prescription products and product approved by NDA and switched to OTC had contained PPA.)
97.) The regulatory design of the OTC procedure has built in delays for FDA to be able to take action against a firm for issues of "safety". (September 2, 1993 53 FR 46589) TFM Amendment to reclassify the Stimulant Laxatives Phenolphthalein from category I (GRASE) to Category II following development of tumors in animals receiving large doses of phenolphthalein (*a grandfathered safe drug) Because of having to deal with products with grandfathered history of "safety" and then later support for efficacy by a DESI and OTC review process, FDA's role with OTC products, including Fleet Phospho-soda Solution, has been dramatically changed from prescription drugs with NDAs. Any removal or change in OTC marketing invokes a significant legal battle with the related OTC industry. (The OTC or nonprescription pharmaceutical industry includes both the name brand manufacturer and all related generic manufacturers.)
98.) Congress deemed OTC products and OTC manufacturers as drug products and firms which require reduced allotment of FDA's limited resources and oversight. The responsibility for oversight of the OTC pharmaceutical firm rests with the firm itself to ensure that its product remains generally recognized as safe and effective and that consumers are not hurt.
99.) OTC drug monographs for active ingredients, both Tentative and Final, are published in the Code of Federal Regulations and are to contain FDA's current minimal recommendations on acceptable active ingredients, dosing, formulations, and labeling. The published monograph will include specific required warnings, as well as testing that should be used for an active ingredient for a specific indication. The monograph information is drawn from various sources including advisory Panels, USP standards, published and unpublished literature, Citizen's Petitions, and product performance history. The FDA does not independently test and develop OTC products or their labels. FDA relies on sponsors of OTC products to update the agency on the safety and efficacy of the therapeutic class of active ingredients. OTC drug monographs are continually being updated by FDA to add additional ingredients, information and labeling.
100.) FDA, to address the deaths and adverse events of which it became aware for Fleet Phospho-soda Solution, restricted the size of the packaging in which it could legally be sold as an OTC product. FDA is able to use negative publicity to help inform consumers and physicians about risks. FDA issued a September 17, 2001 Science Backgrounder titled Safety of Sodium Phosphates Oral Solution intended to inform consumers and physicians about the risks of use of Sodium Phosphate Oral Solution for colon preparation and the risks associated with use of an oral dose greater than 45 mL in 24 hours.
101.) An OTC Tentative or Final Monograph does not prescribe or specify the entire or complete labeling to be used for an active ingredient. The final monograph describes active ingredients not specific finished products. The safety and effectiveness of the labeling for the lay user still rests not with FDA but with the United States manufacturer or labeler of the product. Products with active ingredients which conform to an FDA published monograph may be marketed by a sponsor without first having to obtain FDA's pre-approval. Multiple monograph active ingredients can be combined. Active ingredients not already identified in OTC monographs as "generally recognized as safe and effective" (GRASE ) or which differ from the recommendations specified in the currently published monograph must undergo a separate pre-market review and approval process by FDA as a new drug through a NDA(New Drug Application) to support substantial evidence of "safety and efficacy".
102.) The NDA process is used by FDA for its review purposes of "new" ingredients and drugs even for products which may eventually enter the OTC market for the first time or "new" uses of OTC ingredients. Newer OTC drugs now entering the OTC market are first approved by FDA as an NDA prescription drug and then "switched" to OTC via the NDA process, (Rx to OTC switch). The OTC switch requires that the drug's sponsor can support to FDA that the product can be generally considered as safe and effective (GRASE) when used by the lay consumer for self-treatment.
103.) The first phase of the OTC process is accomplished by advisory review Panels of non-FDA experts reviewing products on the market prior to 1972. The Panels are charged with reviewing the ingredients in nonprescription drug products to determine whether the ingredients could be generally recognized as safe and effective ("GRASE") for use as "self-treatment" by consumers. The Panelists were charged with reviewing claims and recommending labeling including therapeutic indications, dosage instructions, and warnings about the effects and for preventing misuse. The recommendations of the advisory Panels are not binding for FDA. According to the terms of the review, the Panels classified the ingredients into three potential categories:
Category I: Generally Recognized as Safe and Effective (GRASE) for the claimed therapeutic indication.
Category II: Not Generally Recognized as Safe and Effective ("NGRASE") or unacceptable indications;
Category III: insufficient data available to permit final classification.
104.) The second phase of the OTC drug review was the FDA's own review of the ingredients in each class of drugs, based upon the Panel's findings and recommendations, on public comment, and also on new data that may have become available to FDA. The agency in turn publishes its conclusions in the Federal Register in the form of a Tentative Final Monograph (TFM). After publication of the TFM, the Agency allows a period of time for objections or comments to the Agency's proposal or requests for hearings before the Commissioner of FDA. The current TFM is also published in the Code of Federal Regulations applicable to the type of product and active ingredient. The TFM contains FDA's proposed conditions under which a product with be marketed as generally recognized as safe and effective and not considered as misbranded. (*OTC Sodium Phosphates as a GRASE active ingredient in an FDA OTC laxative drug products monograph remains in the TFM stage.)
105.) The third phase of the OTC drug review is the publication of the final regulations in the form of the Final Monograph (FM). The final monograph establishes the conditions under which certain OTC drug product active ingredients are generally recognized as safe and effective and not considered as misbranded.(21 CFR 330.10)
Sec. 330.10 Procedures for classifying OTC drugs as generally recognized as safe and effective and not misbranded, and for establishing monographs.
For purposes of classif
ying over-t

he-counter (OTC) drugs as drugs generally recognized among qualified experts as safe and effective for use and as not misbranded drugs, the following regulations shall apply: (a)Procedure for establishing OTC drug monographs–(1) Advisory review Panels.
All submissions must be in the following format:
VI. A summary of the data and views setting forth the medical rationale and purpose (or lack thereof) for the drug and its ingredients and the scientific basis (or lack thereof) for the conclusion that the drug and its ingredients have been proven safe and effective for the intended use. If there is an absence of controlled studies in the material submitted, an explanation as to why such studies are not considered necessary must be included.
VII. An official United States Pharmacopoeia (USP)-National Formulary (NF) drug monograph for the active ingredient(s) or botanical drug substance(s), or a proposed standard for inclusion in an article to be recognized in an official USP-NF drug monograph for the active ingredient(s) or botanical drug substance(s). Include information showing that the official or proposed compendia monograph for the active ingredient or botanical drug substance is consistent with the active ingredient or botanical drug substance used in the studies establishing safety and effectiveness and with the active ingredient or botanical drug substance marketed in the OTC product(s) to a material extent and for a material time. If differences exist, explain why.
(3) Deliberations of an advisory review Panel. An advisory review Panel will meet as often and for as long as is appropriate to review the data submitted to it and to prepare a report containing its conclusions and recommendations to the Commissioner with respect to the safety and effectiveness of the drugs in a designated category of OTC drugs.
(4) Standards for safety, effectiveness, and labeling. The advisory review Panel, in reviewing the data submitted to it and preparing its conclusions and recommendations, and the Commissioner, in reviewing the conclusions and recommendations of the Panel and the published proposed, tentative, and the final monographs, shall apply the following standards to determine general recognition that a category of OTC drugs is safe and effective and not misbranded:
(i) Safety means a low incidence of adverse reactions or significant side effects under adequate directions for use and warnings against unsafe use as well as low potential for harm which may result from abuse under conditions of widespread availability. Proof of safety shall consist of adequate tests by methods reasonably applicable to show the drug is safe under the prescribed, recommended, or suggested conditions of use. This proof shall include results of significant human experience during marketing. General recognition of safety shall ordinarily be based upon published studies which may be corroborated by unpublished studies and other data.
(ii) Effectiveness means a reasonable expectation that, in a significant proportion of the target population, the pharmacological effect of the drug, when used under adequate directions for use and warnings against unsafe use, will provide clinically significant relief of the type claimed. Proof of effectiveness shall consist of controlled clinical investigations as defined in 314.126(b) of this chapter, unless this requirement is waived on the basis of a showing that it is not reasonably applicable to the drug or essential to the validity of the investigation and that an alternative method of investigation is adequate to substantiate effectiveness. Investigations may be corroborated by partially controlled or uncontrolled studies, documented clinical studies by qualified experts, and reports of significant human experience during marketing. Isolated case reports, random experience, and reports lacking the details which permit scientific evaluation will not be considered. General recognition of effectiveness shall ordinarily be based upon published studies which may be corroborated by unpublished studies and other data.
(iii) The benefit-to-risk ratio of a drug shall be considered in determining safety and effectiveness.
(v) Labeling shall be clear and truthful in all respects and may not be false or misleading in any particular. It shall state the intended uses and results of the product; adequate directions for proper use; and warnings against unsafe use, side effects, and adverse reactions in such terms as to render them likely to be read and understood by the ordinary individual, including individuals of low comprehension, under customary conditions of purchase and use.
(vi) A drug shall be permitted for OTC sale and use by the laity unless, because of its toxicity or other potential for harmful effect or because of the method or collateral measures necessary to its use, it may safely be sold and used only under the supervision of a practitioner licensed by law to administer such drugs.
(5) Advisory review Panel report to the Commissioner. An advisory review Panel may submit to the Commissioner a report containing its conclusions and recommendations with respect to the conditions under which OTC drugs falling within the category covered by the Panel are generally recognized as safe and effective and not misbranded. Included within this report shall be:
(i) A detailed chemical description of the active ingredient(s) that includes a full description of the drug substance, including its physical and chemical characteristics, the method of synthesis (or isolation) and purification of the drug substance, and any specifications and analytical methods necessary to ensure the identity, strength, quality, and purity of the drug substance…
(iii) Reference to the current edition of the U.S. Pharmacopoeia (USP)- National Formulary (NF) or foreign compendiums may help satisfy the requirements in this section.
(2) A list of all countries in which the condition has been marketed. Include the following information for each country. (For a condition that has been marketed OTC in 5 or more countries with a minimum of 5 continuous years of marketing in at least one country, the sponsor may submit information in accordance with paragraph (c)(4) of this section):
(i) How the condition has been marketed (e.g., OTC general sales direct-to-consumer; sold only in a pharmacy, with or without the personal involvement of a pharmacist; dietary supplement; or cosmetic). If the condition has been marketed as a nonprescription pharmacy-only product, establish that this marketing restriction does not indicate safety concerns about its toxicity or other potentiality for harmful effect, the method of its use, or the collateral measures necessary to its use.
(ii) The cumulative total number of dosage units (e.g., tablets, capsules, ounces) sold for each dosage form of the condition. Manufacturers or suppliers of OTC active ingredients may provide dosage unit information as the total weight of active ingredient sold. List the various package sizes for each dosage form in which the condition is marketed OTC. Provide an estimate of the minimum number of potential consumer exposures to the condition using one of the following calculations:
(A) Divide the total number of dosage units sold by the number of dosage units in the largest package size marketed, or
(B) Divide the total weight of the active ingredient sold by the total weight of the active ingredient in the largest package size marketed.
(iii) A description of the population demographics (percentage of various racial/ethnic groups) and the source(s) from which this information has been compiled, to ensure that the condition's use(s) can be reasonably extrapolated to the U.S. population.
(iv) If the use pattern (i.e., how often it is to be used (according to the label) and for how long) varies between countries based on the condition's