1964: The development of new pharmaceuticals was the focus of research at the international pharmaceutical company, G.D. Searle and Company (Farber 1989, page 29). A group working on an ulcer drug was formed including Dr. Robert Mazer, James Schlatter, Arthur Goldkemp and Imperial Chemical. In particular, they were looking for an inhibitor of the gastrointestinal secretory hormone gastrin (Stegink 1984a).
1965: While creating a bioassay, an intermediate chemical was synthesized - aspartylphenylalanine-methyl-ester (aspartame). In December of 1965, while James Schlatter was recrystalling aspartame from ethanol, the mixture spilled onto the outside of the flask. Some of the powder got onto his fingers. Later, when he licked his fingers to pick up a piece of paper, he noticed a very strong sweet taste. He realized that the sweet taste might have been the aspartame. So, believing that the dipeptide aspartame was not likely to be toxic, he tasted a little bit and discovered its sweet taste (Stegink 1984a, page 4). The discovery was reported in 1966, but there was no mention of the sweetness (Furia 1972).
1969: The investigators first reported the discovery of the artificial sweetener in the Journal of the American Chemical Society stating (Mazur 1969):
"We wish to report another accidental discovery of an organic compound with a profound sucrose (table sugar) like taste... Preliminary tasting showed this compound to have a potency of 100-200 times sucrose depending on concentration and on what other flavors are present and to be devoid of unpleasant aftertaste."
Today, hundreds of millions of Americans, and millions more worldwide, consume foods and soft drinks stamped with the NutraSweet "swirl", dump packets of Equal in their coffee, and consume NutraSweet-flavored cereal, puddings, gelatins, cheesecake, chewing gum, diet soft drinks, children's vitamins, chilled juices, and 9,000 other products. So, what is aspartame, a.k.a. NutraSweet, Spoonful, Equal...etc.? aspartyl phenylalanine-methyl ester.
Aspartame (C14H18N2O5) is a compound of three components. These components are methanol, aspartic acid and phenylalanine (the latter being free form amino acids).
Methanol (methyl alcohol or wood alcohol) is a colorless, poisonous, and flammable liquid. It is used for making formaldehyde, acetic acid, methyl t-butyl ether (a gasoline additive), paint strippers, carburetor cleaners for your car's engine, and chloromethanes, et al. This poison can be inhaled from vapors, absorbed through the skin, and ingested.
Methanol is the type of alcohol you read about when people become blind from drinking it. In aspartame, methanol poisoning and poisoning from methanol's breakdown components (formaldehyde and formic acid) can have widespread and devastating effects. This occurs in even small amounts, and is especially damaging when introduced with toxic, free-form amino acids, called excitotoxins.
Methanol is quickly absorbed through the stomach and small intestine mucosa. The methanol is converted into formaldehyde (a known carcinogen). Then, via aldehyde hydrogenase, the formaldehyde is converted to formic acid. These two metabolites of methanol are toxic and cumulative.
Phenylalanine is an amino acid. Well, amino acids are good for us, right? Don't they keep us healthy? The answer is yes, amino acids are necessary for good health, EXCEPT when you separate the individual amino acid from its protein chain, and use it as an "isolate" or by itself.
The Aspartic acid, in aspartame, is also an excitotoxin. An excitotoxin, is a deleterious substance that excites or over-stimulates nerve cells. This occurs in the brain, as well as the peripheral nerves, because aspartic acid, in free form, is an absorption accelerant & easily crosses the blood-brain barrier.
This pathological excitation of nerve cells creates a breakdown of nerve function, as we will see. Basically, they are a group of compounds that can cause special neurons within the nervous system to become overexcited to the point that these cells will die.
That's right, they are excited to death. Excitotoxins include such things as monosodium glutamate (MSG), aspartate, (a main ingredient in NutraSweet), L-cysteine (found in hydrolyzed vegetable protein) and related compounds. What makes this all the more intriguing is that "excitotoxins" appear to play a key role in degenerative nervous system diseases such as Parkinson's disease, Alzheimer's disease, Huntington's, ALS (Lou Gehrig's disease) and many others.
But the story doesn't stop there. It appears that an imbalance of these excitotoxins during critical periods of brain development can result in an abnormal formation of brain pathways; that is, a "miswiring of the brain." This may lead to serious disorders such as behavioral problems (hyperactivity, aggression, attention deficit disorders, learning disorders, poor learning ability, and ADD)-and a lifetime of endocrine problems such as menstrual difficulties, infertility, and premature puberty.
One of the earliest observations seen in animals exposed to large doses was gross obesity. Some neuroscienttists have voiced concern that America's explosion of childhood obesity may be related to excitotoxins in food. Aspartame creates altered brain function, nerve damage, and systemic organ complications. Information collected reveals that aspartame clinically exacerbates any borderline (even yet undetected) predisposing illness, and absolutely complicates certain known medical illnesses like Lupus, Multiple Sclerosis, Parkinson's, diabetes, retinopathies, allergies, mentation disorders, etc.
Aspartame is a toxin, and is unique in this hazardous respect. This in NOT an allergic reaction, but rather a true toxin. No other food can be provided as a comparison to the toxic nature of NutraSweet. Upon closer examination, the available research revealed that the manufacturer (Monsanto) and the FDA are manipulating the public (via the media) into thinking that aspartame is safe. It is not. As an American who trusted the system we all created, as an American who worked for the system, it made me angry that public health has taken a backseat to greed. This is the "engine" that perpetuated this epidemic: the collusion of our government with multi-national conglomerate influence.
G.D. Searle approached Dr. Harry Waisman, Biochemist, Professor of Pediatrics, Director of the University of Wisconsin's Joseph P. Kennedy Jr. Memorial Laboratory of Mental Retardation Research and a respected expert in phenylalanine toxicity, to conduct a study of the effects of aspartame on primates. The study was initiated on January 15, 1970 and was terminated on or about April 25, 1971. Dr. Waisman died unexpectedly in March, 1971.
Seven infant monkeys were given aspartame with milk. One died after 300 days. Five others (out of seven total) had grad mal seizures. The actual results were hidden from the FDA when G.D. Searle submitted its initial applications.
G.D. Searle denied knowledge of or involvement with the initiation, design or performance of the study. Yet, false results were submitted to the FDA like the rest of the 150 G.D. Searle studies (on aspartame and other products), bearing a Searle Pathology-Toxicology project number. Both Dr. Waisman and G.D. Searle were responsible for the study design. A number of false statements were made by G.D. Searle including that the animals were unavailable for purchase for autopsy after the termination of the study.
The FDA banned the sweetener cyclamate, 1969. Robert Scheuplein, who was the acting Director of FDA's Toxicological Services Center for Food Safety and Applied Nutrition was quoted as saying "the decision was more a matter of politics than science."
Neuroscientist and researcher John W. Olney found that oral intake of glutamate, aspartate and cysteine, all excitotoxic amino acids, cause brain damage in mice (Olney 1970). Dr. John W. Olney informed G.D. Searle that aspartic acid caused holes in the brains of mice.
Ann Reynolds, a researcher who was hired by G.D. Searle and who has done research for the Glutamate (MSG) Association, and was asked to confirm Dr. Olney's tests. Dr. Reynolds confirmed aspartame's neurotoxicity in infant mice.
Excitotoxic compounds like MSG, aspartate, cysteine seem to create hypothalamic lesions, particularly in young animals. The reason for the latter is likely the fact that the blood brain barrier closes most slowly (if ever completely) around structures like the hypothalamus. The outcome for such animals (rats) was obesity, severe behavioral changes, etc.
G.D. Searle did not inform the FDA of this study until after aspartame's approval. None of the tests submitted by G.D. Searle to the FDA contradicted these findings (Olney 1970, Gordon 1987, page 493 of US Senate 1987).
An internal G.D. Searle memo laid out the strategy for getting aspartame approved (Helling 1970):
At this meeting [with FDA officials], the basic philosophy of our approach to food and drugs should be to try to get them to say, "Yes," to rank the things that we are going to ask for so we are putting first those questions we would like to get a "yes" to, even if we have to throw some in that have no significance to us, other than putting them in a yes saying habit.
We must create affirmative atmosphere in our dealing with them. It would help if we can get them or get their people involved to do us any such favors. This would also help bring them into subconscious spirit of participation.
FDA Toxicologist Dr. Adrian Gross came upon some irregularities in the submitted tests of the G.D. Searle drug Flagyl. G.D. Searle did not respond for another two years. Their response raised serious questions about the validity of their tests (Gross 1975, page 35)
On March 5, 1973, G.D. Searle's petition to the FDA for approval to market aspartame as a sweetening agent was published in the Federal Register (1973).
On March 21, 1973 the MBR report was submitted to G.D. Searle. Background: In August of 1970, G.D. Searle conducted two 78-week toxicity studies on rats for what was to become a best-selling heart medication, Aldactone. One study was conducted at G.D. Searle and one at Hazelton Laboratories.
In March 1972, the rats were autopsied and the pathology slides were analyzed. For confirmation of the results, G.D. Searle sent the slides to Biological Research, Ltd. where board certified pathologist, Dr. Jacqueline Mauro examined the data. She discovered that the drug appeared to induce tumors in the liver, testes, and thyroid of the rats. The report submitted to G.D. Searle by Dr. Mauro was known as the MBR Report. These statistically significant findings were confirmed by G.D. Searle's Mathematics-Statistics Department.
Instead of submitting these alarming findings to the FDA, G.D. Searle contracted with another pathologist, Dr. Donald A. Willigan. He was given 1,000 slides to examine. The Willigan Report was more to G.D. Searle's liking because it revealed a statistically significant increase in thyroid and testes tumors, but not in liver tumors. Liver tumors are of much more concern to the FDA. The Willigan Report was immediately submitted to the FDA. G.D. Searle did not disclose the MBR Report to the FDA until August 18, 1975, 27 months after it had been given to G.D. Searle.
At first, G.D. Searle claimed that they did not submit the MBR Report to the FDA because of an "oversight."
The FDA Commissioner from 1972 to 1976, Alexander Schmidt, M.D. felt that "Superficially, it seemed like, if there would ever be a safe kind of product, that would be it. The idea that two naturally-occurring amino acids could harm someone in relatively small amounts...."
In an FDA memorandum dated September 12, 1973, Martha M. Freeman, MD of the FDA Division of Metabolic and Endocrine Drug Products addressed the adequacy of the information submitted by G.D. Searle in their petition to approve aspartame (Freeman 1973):
"Although it was stated that studies were also performed with diketopiperazine [DKP] an impurity which results from acid hydrolysis of Aspartame, no data are provided on this product."
Commenting on one particular single dose study:
"It is not feasible to extrapolate results of such single dose testing to the likely condition of use of Aspartame as an artificial sweetener."
It is important to note that Dr. Freeman pointed out the inadequacy of single-dose tests of aspartame as early as 1973.
Matalon said, "Let us say cigarettes were invented today, and you give 20 people two packs a day and after six weeks, no one has cancer, would you say that it was safe? That's what they did with NutraSweet."
Since then, the NutraSweet Company has flooded the scientific community with single-dose studies.
"Chemistry - No information is provided other than formulae for Aspartame and its diketo-piperazine."
Pharmacology - Reference is made to 2 year rat studies, but no data are provided on acute or chronic toxicity."
"Clinical - No protocols or curriculum vitae information are provided for the 10 completed clinical studies. Results are reported in narrative summary form, and tabulations of mean average values only.
No information is given as to the identity of the reporting labs, methodology (except rarely), or normal values. (Reported units for several parameters cannot be verified at this time.)
"No pharmacokinetic data are provided on absorption, excretion, metabolism, half-life; nor bioavailability of capsule vs. food-additive administration."
Dr. Freeman concludes:
"1. The administration of Aspartame, as reported in these studies at high dosage levels for prolonged periods, constitutes clinical investigational use of a new drug substance."
"2. The information submitted for our review is inadequate to permit a scientific evaluation of clinical safety."
She went on to recommend that marketing of aspartame be contingent upon proven clinical safety of aspartame. The FDA Bureau of Foods rejected Dr. Freeman's recommendation.
(Congressional Record 1985a)
Construction of a large aspartame manufacturing plant in Augusta, Georgia was halted. It was thought that aspartame's uncertain regulatory future was the main reason for the stopping of construction (Farber 1989, page 47). In the 1973 G.D. Searle Annual Report, an executive stated that "commercial quantities of the sweetener will be supplied from the enlarged facility of Ajinomoto."
Ajinomoto is the inventor and main producer of the food additive MSG.
Ninety of the 113 aspartame studies which were submitted by G.D. Searle to the FDA were conducted in the early to mid-1970's. All of the tests that were described by the FDA as "pivotal" were conducted during this time. Eighty percent of these tests were conducted by G.D. Searle or by their major contractor, Hazleton Laboratories, Inc.
(Graves 1984, page S5497 of Congressional Record 1985a).
Dr. J. Richard Crout, the acting director of the FDA Bureau of Drugs stated that "The information submitted for our review was limited to narrative clinical summaries and tabulated mean values of laboratory studies. No protocols, manufacturing controls information or preclinical data were provided.
Such deficiencies in each area of required information precluded a scientific evaluation of the clinical safety of this product...."
Dr. John Olney and Consumer Interest attorney, James Turner, Esq. met with G.D. Searle to discuss the results of Olney's experiments. G.D. Searle representative's claim that Olney's data raises no health concerns.
On July 26, 1974, just 15 months after Searle petitioned for approval, FDA commissioner Alexander Schmidt approved aspartame use in dry foods, allowing a 30-day period for public hearings and comment. He acted on a strong endorsement from the Bureau of Foods, now called the Center for Food Safety and Applied Nutrition (CFSAN).
It was not approved for baking goods, cooking, or carbonated beverages. This approval came despite the fact that FDA scientists found serious deficiencies in all of the 13 tests related to genetic damage which were submitted by G.D. Searle.
At that point, consumer attorney Turner, author of a 1970 book about food additives, objected to the short comment period.
Turner was joined in his protest by a now-defunct public interest group and by Dr. John Olney, a Washington University neuropathologist who had linked aspartame to brain lesions in mice.
Schmidt promptly froze the approval. In an action that was the first of its kind, he ordered that a Public Board of Inquiry be named to look into aspartame. Schmidt also had been alerted to conflicts between Searle research reports and conclusions from independent animal studies that the firm's anti-infective drug, Flagyl and its cardiovascular drug Aldactone may cause cancer. He named a Bureau of Drugs task force to investigate.
Philip Brodsky, the unit's since-retired lead investigator, said aspartame was included in a broad inquiry into Searle animal studies on five drugs and the Copper-7 intrauterine device to surprise the company. "We didn't think they'd expect us to cover it."
The task force assailed Searle's conduct of research on most of the products, including aspartame, in a searing, 84-page report.
"At the heart of the FDA's regulatory process," the report said, "is its ability to rely upon the integrity of the basic safety data submitted by sponsors of regulated products. Our investigation clearly demonstrates that, in the G.D. Searle Co., we have no basis for such reliance now."
The task force charged, for example, that the company removed tumors from live animals and stored animal tissues in formaldehyde for so long that they deteriorated. Instead of performing autopsies on rhesus monkeys that suffered seizures after being fed aspartame, the company had financed a new monkey study with a different methodology that showed no problems.
For the next seven years, Searle's petition was tied up in reviews by the task force and other sharply critical FDA panels.
At the task force's request, Richard Merrill, the FDA's general counsel, demanded in a letter that Samuel Skinner, the U.S. attorney in Chicago, open a grand jury investigation of Searle and three of its employees.
One Searle official named by Merrill was Robert McConnell, who had been director of Searle's Department of Pathology and Toxicology and oversaw most of the company's aspartame research.
McConnell's Detroit lawyer, Gerald Wahl, said that as the inquiries heated up, his client was suddenly awarded a $15,000 bonus and asked to take a three-year sabbatical by director Wesley Dixon. Wahl said Dixon told McConnell he had become a "political liability," a remark Dixon later denied making.
McConnell received his annual salary of more than $60,000 during the sabbatical at the Massachusetts Institute of Technology, but he never got his job back, and ended up suing the company, Wahl said.
"I've represented hundreds of executives, but I've never seen anybody get the deal that McConnell got," he said. "When you boil it all down, they were looking for continued support from McConnell during the inquiries."
G.D. Searle's responses to queries about the testing of their drug Flagyl, serious and unexpected side effect from other drugs they developed, and information from Dr. John Olney's studies started a controversy within the FDA as to the quality and validity of G.D. Searle's test of aspartame and pharmaceuticals (Congressional Record 1985a).
In July 1975, the FDA Commissioner, Dr. Alexander Schmidt appointed a special Task Force to look at 25 key studies for the drugs Flagyl, Aldactone, Norpace, and the food additive aspartame. Eleven of the pivotal studies examined involved aspartame. All of the studies whether conducted at G.D. Searle or Hazleton Laboratories were the responsibility of the Pathology-Toxicology Department at G.D. Searle. (Gross 1987a, page 430 of US Senate 1987).
The special Task Force was headed by Philip Brodsky, FDA's Lead Investigator and assisted by FDA Toxicologist, Dr. Adrian Gross. The Task Force was especially interested in "pivotal" tests as described in an article from Common Cause Magazine by Florence Graves (Graves 1984, page S5499 of Congressional Record 1985a):
"Before the task force had completed its investigation in 1976, Searle had submitted the vast majority of the more than 100 tests it ultimately gave the FDA in an effort to get aspartame approved.
These included all test ever described as 'pivotal' by the FDA. About half the pivotal tests were done at Searle; about one-third were done at Hazleton Laboratories. 'Pivotal' tests include long-term (two-year) tests such as those done to determine whether aspartame might cause cancer.
Former FDA commissioner Alexander Schmidt said in a recent interview that if a pivotal test is found to be unreliable, it must be repeated 'Some studies are more important than others, and they have to be done impeccably,' Schmidt said."
G.D. Searle executives admitted to "payments to employees of certain foreign governments to obtain sales of their products." (Searle 1975)
Consumer lawyer Turner said, "The notion that an industrial company would take large sums of money and parcel it out to scientific consulting firms and university departments, who they consider to be personal and commercial allies is an unconscionable way to ensure the safety of the American food supply."
He said the NutraSweet experience shows that "the entire system of the way scientific research is done needs to be carefully investigated, evaluated, and revamped."
Food industry officials also said most studies financed by Searle or the NutraSweet Co. have been arranged as contracts, rather than grants. Smith said the company often uses contracts "to accomplish a specific research task."
James Scala, former director of health sciences for the General Foods Corp., a major NutraSweet user, said that a scientist working under contract became "more of an arm of the Searle research group than a grantee."
On July 10, 1975, Senator Edward Kennedy chaired a hearing on drug-related research before the Senate Subcommittee on Health of the Committee on Labor and Public Welfare (US Senate 1975). Preliminary reports of discrepancies discovered about G.D. Searle were discussed.
The findings of the FDA Task Force were later presented at further hearings on January 20, 1976 (US Senate 1976a) and April 8, 1976 (US Senate 1976b).
Chief investigator Brodsky said that "politicized" handling of the task force disclosures, at hearings chaired by Sen. Edward Kennedy D-Mass., was one reason he retired in 1977. He said the main witnesses, Searle executives, and top FDA officials uninvolved in the investigation gave "the wrong answers to the wrong questions"...They didn't even let the experts answer the questions.
On December 5, 1975, Dr. John Olney and James Turner waived their right to a hearing at the suggestion of the FDA General Counsel after the FDA and G.D. Searle agreed to hold a Public Board Of Inquiry (PBOI) (Federal Register 1975).
On December 5, 1975, the FDA put a hold on the approval of aspartame due to the preliminary findings of the FDA Task Force. The Public Board of Inquiry is also put on hold.
The evidence of the aspartame pivotal studies were protected under FDA seal on December 3, 1975 (Sharp 1975).
G.D. Searle had invested 19.7 million dollars in an incomplete production facility and 9.2. million dollars in aspartame inventory. On December 8, 1975, stockholders filed a class action lawsuit alleging that G.D. Searle had concealed information from the public regarding the nature and quality of animal research at G.D. Searle in violation of the Securities and Exchange Act (Farber 1989, page 48).
On January 7, 1976, G.D. Searle submitted to the FDA their proposal for the adoption of "Good Laboratory Practices" (Buzzard 1976b). G.D. Searle's input was used in FDA's adoption of Good Laboratory Practices.
In March 1976, the FDA Task Force completed a 500-page report with 15,000 pages of exhibits (80-page summary) to the FDA after completing their investigation (Schmidt 1976c, page 4 of US Senate 1976b).
A preliminary statement about the breadth of the investigation from FDA Toxicologist and Task Force team member, Dr. Andrian Gross before the US Senate (Gross 1987a, page 1-2):
"Practices that were noted in connection with any given such study were quite likely to have been noted also for other studies that were audited, and this was a situation which was in no way unexpected: after all, the set of all such studies executed by that firm from about 1968 to the mid- 1970's were conducted in essentially the same facilities, by virtually the same technicians, professional workers and supervisors, and the nature of such studies does not differ much whether a food additive or a drug product is being tested for safety in laboratory animals.
It is in this sense, therefore, that the overall conclusion summarized at the beginning of the Searle Task Force Report have relevance to all the studies audited in 1975 (whether they had references to aspartame or to any of the six drug products of Searle's) and, by extension, to the totality of experimental studies carried out by that firm around that time - 1968 to 1975."
A few of the conclusions of the FDA Task Force (Gross 1987a, page 2-3):
"At the heart of FDA's regulatory process is its ability to rely upon the integrity of the basic safety data submitted by sponsors of regulated products. Our investigation clearly demonstrates that, in the (case of the) GD Searle Company, we have no basis for such reliance now."
"We have noted that Searle has not submitted all the facts of experiments to FDA, retaining unto itself the unpermitted option of filtering, interpreting, and not submitting information which we would consider material to the safety evaluation of the product ... . Finally, we have found instances of irrelevant or unproductive animal research where experiments have been poorly conceived, carelessly executed, or inaccurately analyzed or reported."
"Some of our findings suggest an attitude of disregard for FDA's mission of protection of the public health by selectively reporting the results of studies in a manner which allay the concerns of questions of an FDA reviewer."
"Unreliability in Searle's animal research does not imply, however, that its animal studies have provided no useful information on the safety of its products. Poorly controlled experiments containing random errors blur the differences between treated and control animals and increase the difficulty of discriminating between the two populations to detect a product induced effect.
A positive finding of toxicity in the test animals in a poorly controlled study provides a reasonable lower bound on the true toxicity of the substance.
The agency must be free to conclude that the results from such a study, while admittedly imprecise as to incidence or severity of the untoward effect, cannot be overlooked in arriving at a decision concerning the toxic potential of the product."
A few of the relevant findings summarized from various documents describing the FDA Task Force Report:
- "Excising masses (tumors) from live animals, in some cases without histologic examination of the masses, in others without reporting them to the FDA." (Schmidt 1976c, page 4 of US Senate 1976b) Searle's representatives, when caught and questioned about these actions, stated that "these masses were in the head and neck areas and prevented the animals from feeding." (Buzzard 1976a)
- "Failure to report to the FDA all internal tumors present in the experimental rats, e.g., polyps in the uterus, ovary neoplasms as well as other lesions." (Gross 1987a, page 8).
- G.D. Searle "stored animal tissues in formaldehyde for so long that they deteriorated." (Gordon 1987, page 496 of US Senate 1987; US Schmidt 1976c, page 25, 27 of US Senate 1976b)
- "Instead of performing autopsies on rhesus monkeys that suffered seizures after being fed aspartame, the company had financed a new monkey seizure study with a different methodology that showed no problems." (Gordon 1987, page 496 of US Senate 1987)
- "Reporting animals as unavailable for necropsy when, in fact, records indicate that the animals were available but Searle choose not to purchase them." (Schmidt 1976c, page 5 of US Senate 1976b)
- Animals which had died were sometimes recorded as being alive and vice versa. "These include approximately 20 instances of animals reported as dead and then reported as having vital signs normal again at subsequent observation periods." (Gross 1985, page S10835)
- "Selecting statistical procedures which used a total number of animals as the denominator when only a portion of the animals were examined, thus reducing the significance of adverse effects." (Schmidt 1976c, page 4 of US Senate 1976b)
- G.D. Searle told the FDA that 12 lots of DKP were manufactured and tested in one study, yet only seven batches were actually made. (Gross 1985, page S10835)
- "Significant deviations from the protocols of several studies were noted which may have compromised the value of these studies ... In at least one study, the Aspartame 52 weeks monkey study, the protocol was written after the study had been initiated." (Gross 1985, page S10835)
- "It is significant to note that the Searle employee responsible for reviewing most of the reproduction studies had only one year of prior experience, working on population dynamics of cotton tail rabbits while employed by Illinois Wildlife Service. In order to prepare him for this title of 'Senior Research Assistant in Teratology' (fetal damage) Searle bought him books to read on the subject and also sent him to a meeting of the Teratology Society. This qualified him to submit 18 of the initial tests to the FDA, in addition to training an assistant and 2 technicians. He certainly must have kept them busy because Searle claimed that 329 teratology examinations were conducted in just 2 days. He estimated that he himself examined about 30 fetuses a day, but officials for the Center for Food and Applied Nutrition could never determine how that was possible."
- "In each study investigated, poor practices, inaccuracies, and discrepancies were noted in the antemortem phases which could compromise the study."
- "Presenting information to FDA in a manner likely to obscure problems, such as editing the report of a consulting pathologist ... Reporting one pathology report while failing to submit, or make reference to another usually more adverse pathology report on the same slide." (Schmidt 1976c, page 4-5 of US Senate 1976b)
- Animals were not removed from the room during the twice per month exterminator sprayings. (Gross 1985, page S10836 of Congressional Record 1985b)
- Often the substance being tested which was given to the animals was not analyzed or tested for homogeneity. "No records were found to indicate that any treatment mixtures used in the studies were ever tested or assayed for pesticide content ... Running inventory records for either treatment mixtures or the test compounds used in treatment mixtures are not maintained."
- In the Aspartame (DKP) 115 week rat study the written observations of the pathology report was changed by the supervising pathologist, Dr. Rudolph Stejskal even though he was not physically present during the autopsies and could not have verified the observations of the pathologist who did perform the autopsies. The pathologist who did perform some of the autopsies had no formal training for such procedures.
- "Contrary to protocol, slides were not prepared of this [unusual lesions from the Aspartame (DKP) study) tissue for microscopic examinations ... .."
- "In the Aspartame 46 weeks hamster study, blood samples reported in the submission to FDA as 26 week values (for certain specified animals) were found by our investigators as being, in fact, values for different animals which were bled at the 38th week. Many of the animals for which these values were reported (to the FDA) were dead at the 38th week." (Gross 1985, page S10838)
- "It is apparent from the report, that the Appendix portion contains all the individual (animal) values of clinical lab data available from the raw data file. A selected portion of these values appears to have been used in computing group means (which were reported to the FDA). It is not clear what criteria may have been used for selecting a portion of the data or for deleting the others in computing the means (reported to the FDA)." (Gross 1985, page S10838 of Congressional Record 1985b)
- "Searle technical personnel failed to adhere to protocols, make accurate observations, sign and date records, and accurately administer the product under test and proper lab procedures."
- [There were] "clerical or arithmetic errors which resulted in reports of fewer tumors."
- [G.D. Searle] "delayed the reporting of alarming findings."
FDA Toxicologist and Task Force member, Dr. Andrian Gross stated:
"They [G.D. Searle] lied and they didn't submit the real nature of their observations because had they done that it is more than likely that a great number of these studies would have been rejected simply for adequacy. What Searle did, they took great pains to camouflage these shortcomings of the study.
As I say, filter and just present to the FDA what they wished the FDA to know and they did other terrible things for instance animals would develop tumors while they were under study. Well they would remove these tumors from the animals."
FDA Lead Investigator and Task Force Team Leader, Phillip Brodsky described the 1975 FDA Task Force members as some of the most experienced drug investigators. He went on to state that he had never seen anything as bad as G.D. Searle's studies.
The report quoted a letter written to G.D. Searle on July 15, 1975 from its consultant in reproduction and teratology, Dr. Gregory Palmer, in regards to a review of some of G.D. Searle's reproductive studies submitted to the FDA; (as noted in the Congressional record)
"Even following the track you did, it seems to me you have only confounded the issue by a series of studies most of which have severe design deficiencies or obvious lack of expertise in animal management. Because of these twin factors, all the careful and detailed examination of fetuses, all the writing, summarization and resummarization is of little avail because of the shaky foundation."
G.D. Searle officials noted that Dr. Palmer did not look at all of the teratology studies (Searle 1976b, page 21). However, there is no credible evidence that would lead a reasonable person to believe that the studies which were not presented to Dr. Palmer were much better. In fact, the evidence shows that it is very likely that all of the studies were abysmal.
The FDA Commissioner at the time, Alexander Schmidt stated (Graves 1984, page S5497 of Congressional Record 1985a):
"[Searle's studies were] incredibly sloppy science. What we discovered was reprehensible."
Dr. Marvin Legator, professor and director of environmental toxicology at the University of Texas and the pioneer of mutagenicity testing at the FDA from 1962 to 1972 was asked by Common Cause Magazine to review the FDA investigation results of G.D. Searle's tests page (Congressional Record 1985a):
"[All tests were] scientifically irresponsible [and] disgraceful.
I'm just shocked that that kind of sloppy [work] would even be sent to FDA, and that the FDA administrators accepted it. There is no reason why these tests couldn't have been carried out correctly. It's not that we are talking about some great scientific breakthrough in methodology."
Senator Edward Kennedy at the April 8, 1976 hearings before the Senate Subcommittee on Labor and Public Welfare stated (Se. Ted Kennedy 1976):
"The extensive nature of the almost unbelievable range of abuses discovered by the FDA on several major Searle products is profoundly disturbing."
"In all of the studies at Searle which have been examined by the FDA in its investigation, the scope of the material being considered included seven years of observation, from 1968 to date, in 57 studies involving more than 5,700 animals with over 228 million observations and calculations."
However, their deliberate misconduct and "lies" (as put by FDA Investigator, Dr. Adrian Gross) invalidated their experiments for the following reasons:
- Many of the problems with the studies included horrendous experimental designs, questions regarding dosage given, loss of animal tissue and data, etc., etc., which invalidates entire experiments and causes what they claim to be 4 million observations and calculations per study (average) to become irrelevant.
- Only the key aspartame studies were looked at. It is almost a certainty that the non-key aspartame studies were equally flawed. Therefore, this would invalidate the "hundreds of millions" of observations and calculations made during these studies.
- The difference between a study showing no statistical difference and a significant statistical difference is often only a few observations or calculations. Therefore, had the myriad of other serious experimental errors not occurred (as detailed above), the observation and calculation mistakes in each experiment investigated would, by themselves, invalidate most of the key studies.
- It is highly unlikely that the FDA Investigative teams found all of the problems with G.D. Searle's studies. G.D. Searle seemed so intent on covering up their misconduct, that it is quite likely that they were able to hide many of the problems from the FDA.
A series of poorly conceived, flawed studies funded by G.D. Searle were published in Volume 2 (1976) of the Journal of Toxicology and Environmental Health. An Associate Editor of this scientific journal was Robert G. McConnell, the Director of G.D. Searle's Department of Pathology and Toxicology (the department responsible for monitoring the quality of G.D. Searle's pre-approval tests investigated by the 1975 FDA Task Force). Mr. McConnell's story continues later in 1977.
Another G.D. Searle employee, Carl R. Mackerer was an editor of the journal. Another editor of the journal was Thomas R. Tephly, the person responsible for conducting a series of badly flawed blood methanol and formate measurements in NutraSweet-funded studies over the last 15 years.
In July 1976, the FDA decided to investigate 15 key aspartame studies submitted by G.D. Searle in which the 1975 FDA Task Force discovered problems. Three (3) of the studies were investigated at the FDA (E5, E77/78, E89) by a 5-member Task Force headed by FDA veteran Inspector, Jerome Bressler.
On August 4, 1976, G.D. Searle representatives met with the FDA and convinced them to allow G.D. Searle to hire a private agency, University Associated for Education in Pathology (UAREP), and pay them $500,000 to "validate" the other 12 studies.
According the FDA Commissioner during the early 1980s, Arthur Hull Hayes, the UAREP investigation was to "make sure that the studies were actually conducted."
As described by Florence Graves:
"The pathologists were specifically told that they were not to make a judgment about aspartame's safety or to look at the designs of the tests. Why did the FDA choose to have pathologists conduct an investigation when even some FDA officials acknowledged at the time that UAREP had a limited task which would only partially shed light on the validity of Searle's testing? The answer is not clear.
"Dr. Kenneth Endicott, Director of UAREP, said in an interview that the FDA had 'reasons to suspect' that Searle's tests 'were not entirely honest.' Because the FDA 'had doubts about [Searle's] veracity,' Edicott said, officials wanted UAREP 'to determine whether the reports were accurate.'
"FDA scientist Dr. Adrian Gross, in a letter to an FDA official, said, 'speaking as a pathologist, it seemed questionable that the group could do the kind of comprehensive investigation that was required. He pointed in particular to a variety of issues that needed to be investigated. He said some of these would involve closely questioning administrators and lab technicians about their practices. Since many important issues that should be investigated 'have nothing to do with pathology,' he said, only trained FDA investigators were qualified to do a comprehensive evaluation of the testing... .
"Meanwhile, an interview with Endicott indicates that Adrian Gross was right: the pathologists couldn't-and didn't-carry out a comprehensive review... . As former FDA Commissioner Alexander Schmidt put it in a recent interview, UAREP looked at the slides to determine whether they had been misrepresented, but didn't look at the conduct of the experiments in depth. The 1975 [FDA] task force investigation looked at the conduct of the experiments in depth, but did not look at the slides... . . Endicott agreed ... 'We could only look at what was there-the tissues.'
The findings of this investigation where released in the Bessler Report in August 1977 (see below).
1977 OUR POLITICAL PROCESS AT WORK:
Donald Rumsfeld, who was a former member of the U.S. Congress and the Chief of Staff in the Gerald Ford Administration, was hired as G.D. Searle's President. Attorney James Turner, Esq. alleged that G.D. Searle hired Rumsfeld to handle the aspartame approval difficulties as a "legal problem rather than a scientific problem." (US Senate 1987).
Rumsfeld hired: John Robson as Executive Vice President. He was a former lawyer with Sidley and Austin, Searle's Law Firm and also served as chairman of the Civil Aeronautics Board, which was then connected to the Department of Transportation.
Robert Shapiro as General Counsel. He is now head of Searle's NutraSweet Division. He had been Robson's Special Assistant at the Department of Transportation.
William Greener, Jr., as Chief Spokesman. He was a former spokesman in the [Gerald] Ford White House.
Donald Rumsfeld is now on the Board of Directors of the Chicago Tribune which recently wrote a glowing article about the NutraSweet Company.
On January 10, 1977, FDA Chief Counsel Richard Merrill recommended to U.S. Attorney Sam Skinner in a 33-page letter detailing violations of the law that a grand jury be set up to investigate G.D. Searle. In the letter, Merrill stated:
"We request that your office convene a Grand Jury investigation into apparent violations of the Federal Food, Drug, and Cosmetic Act, 21 U.S..C. 331(e), and the False Reports to the Government Act, 18 U.S.C. 1001, by G.D. Searle and Company and three of its responsible officers for their willful and knowing failure to make reports to the Food and Drug Administration required by the Act, 21 U.S.C. 355(i), and for concealing material facts and making false statements in reports of animal studies conducted to establish the safety of the drug Aldactone and the food additive Aspartame."
All of the G.D. Searle studies were abysmal as discussed earlier. However, there were two studies where the violations of the law appeared to be especially flagrant. The two studies cited by Merrill were the 52-week toxicity study on infant monkeys performed by Dr. Waisman which G.D. Searle withheld key information from the FDA and the 46-week toxicity study of hamsters where G.D. Searle had taken blood from healthy animals at the 26th week and claimed that the tests had actually been performed at the 38th week.
Many of the animals from which G.D. Searle claimed had blood drawn from were actually dead at the 38th week. See earlier discussion for references.
On January 26, 1977, G.D. Searle's law firm, Sidley & Austin, requested a meeting with U.S. Attorney Samuel Skinner before a grand jury is convened. One representative of Sidley & Austin at that meeting was Newton Minow who is currently on the Board of Directors at the Chicago Tribune.
On March 8, 1977, in a confidential memo to aides, while he was supposed to be pushing for fraud indictments against G.D. Searle, U.S. Attorney Samuel Skinner stated that he had begun preliminary employment discussions with G.D. Searle's law firm Sidley & Austin. page 497 of US Senate 1987;
On April 13, 1977, a U.S. Justice Department memo urged U.S. Attorney Samuel Skinner to proceed with grand jury investigations of G.D. Searle. The memo points out that the Statute of limitations on prosecution would run out shortly (October 10, 1977 for the Waisman monkey study and December 8, 1977 for the hamster study.
Samual Skinner withdrew from the G.D. Searle case and Assistant U.S. Attorney William Conlon was then assigned to the Grand Jury investigation (Gordon 1987, page 497 of US Senate 1987).
On July 1, 1977, U.S. Attorney Samuel Skinner left his job to work for the G.D. Searle law firm Sidley & Austin. Thomas Sullivan was appointed as Samuel Skinner's successor page 497 of US Senate 1987).
Meanwhile, Much like the earlier team, the five-member FDA task force, headed by veteran Chicago inspector Jerome Bressler, assailed the quality of animal tests into whether the substance might cause birth defects and tumors. The report said Searle laboratory employee Raymond Schroeder, who worked on related research, first told investigators the feed in the study of the aspartame breakdown product DKP (diketopiperazine) was so inadequately mixed it appeared the rats could "discriminate" and avoid eating the DKP. Schroeder, who has worked for another company since 1975, later backed off his statement. He told UPI, "I just didn't feel qualified to speak on something I didn't work on...There's no one twisting my arm."
In August 1977, the Bressler Report pertaining to three key aspartame studies, E5, E77/78 and E89, was released. Some of the findings from the three studies reviewed by the Bressler-led FDA Task Force include.
- In one study, 98 of the 196 animals died but were not autopsied until as much as one year later. Because of the delay, much of the animal tissue could not be used and at least 20 animals had to be excluded from postmortem examinations.
- The original pathology sheets and the pathology sheets submitted to the FDA showed differences for 30 animals.
- One animal was reported alive at week 88, dead from week 92 through week 104, alive at week 108, and finally dead at week 112.
- An outbreak of an infectious disease was not reported to the FDA.
- Tissue from some animals were noted to be unavailable for analysis on the pathology sheets, yet results from an analysis of this "unavailable" tissue was submitted to the FDA.
- There was evidence that the diet mix was not homogeneous allowing the animals to eat around the test substance. This evidence included a picture and statements by a lab technician.
- Fifteen fetuses from animals in one experiment were missing.
- Sections from the animals were too thick for examination.
- There was no documentation on the age or source of the test animals.
- There was no protocol until one of the studies was well underway.
- Animals were not permanently tagged to prevent mix-ups.
- Some laboratory methods were changed during the study, but not documented.
A G.D. Searle pathologist referring to the DKP study was quoted by investigators as saying:
"You should have seen things when this study was run - there were five studies being run at one time - things were a mess!"
The leader of the Task Force, Jerome Bressler, was quoted as saying:
"The question you have got to ask yourself is: Because of the importance of this study, why wasn't greater care taken? The study is highly questionable because of our findings. Why didn't Searle, with their scientists, closely evaluate this, knowing fully well that the whole society, from the youngest to the elderly, from the sick to the unsick... will have access to this product."
Howard Roberts, acting director of FDA's Bureau of Foods, appointed a five-person task force to review the Bressler team's findings pending a decision on whether to throw out the three tumor and birth-defect studies.
Jacqueline Verrett, a senior FDA scientist on the review team, said members were barred from stating opinions about the research quality. "It was pretty obvious that somewhere along that line they (bureau officials) were working up to a whitewash," she said.
"I seriously thought of just walking off of that task force." Verrett, now a private consultant, said that she and other members wanted to "just come out and say that this whole experiment was a disaster and should be disregarded."
But on September 28, 1977, the panel reported that deviations between Searle's raw data and its FDA submissions were "not of such magnitude as to alter its conclusion."
Verrett said the bureau's intent seemed to be "to tone down what was really found." She noted the bureau felt pressure because safety concerns also had been raised about cyclamate, another alternative for the cancer-linked sugar substitute, saccharin.
In October, 1978, a year after ordering the review that helped get Searle's petition back on track, Robert's (acting Director of Bureau of Foods) quit to become vice president at the National Soft Drink Association. The NSDA's members later marketed a stream of NutraSweet-flavored diet soft drink products.
Reached at NSDA, Roberts dismissed Verrett's criticism, asserting the task force report "really was of no importance." He said he had no concerns about the appearance of his taking the NSDA job, stressing he does not represent NSDA before the FDA. "I sleep well at night," he said.
For each of the major discrepancies found by the Bressler-led Task Force - those listed above and many others - there was a comment in the FDA Bureau of Foods Report minimizing the problem. It seemed that no matter how serious the mistakes were, the FDA Bureau of Foods was determined to accept the studies by G.D. Searle.
The experimental errors as described above were so bad that it proved difficult to minimize all of the major errors in these key studies.
In some cases, the best that the CFSAN could do was to say that "The Task Force could find no evidence that this was a deliberate attempt to influence the study." or "It could not be determined if the results would have been altered...."
The Senior Scientist of the FDA Bureau of Foods Task Force, Jacqueline Verrett had left the FDA. Speaking for the UPI Investigation into Aspartame, she said, 'I seriously thought of just walking off of that task force.' Verrett, now a private consultant, said that she and other members wanted to 'just come out and say that this whole experiment was a disaster and should be disregarded.'
In her testimony before the U.S. Senate, Dr. Verrett stated the following (Verrett 1987):
"This authentication was hence intended to verify that the submitted data had not been altered; that it reflected the actual outcome of the study, and that it did not change substantially, particularly in a statistical sense, the various parameters from which the conclusion of safety had been derived.
"Our analysis of the data in this manner revealed that in these three studies, there were really no substantial changes that resulted, although in numerous instances, a definitive answer could not be arrived at because of the basic inadequacies and improper procedures used in the execution of these studies.
"I would like to emphasize the point that we were specifically instructed not to be concerned with, or to comment upon, the overall validity of the study. This was to be done in a subsequent review, carried out at a higher level... . . "It would appear that the safety of aspartame and its breakdown products has still not been satisfactorily determined, since many of the flaws cited in these three studies were also present in all of the other studies submitted by Searle... ...
"Well, they told us in no uncertain terms that we were not to comment on the validity of it. And I hoped, although having been there at that point for 19 years, I should have known better, that there really would be an objective evaluation of this beyond the evaluation that we did.
"I do not feel that that was done, based on what I have read in the GAO report that I have looked at and so forth. They definitely did not objectively evaluate these studies, and I really think it should have been thrown out from day one.
"We were looking at a lot of little details and easy parameters in this study, when the foundation of the study, the diet and all of these other things, were worthless. We were talking about the jockey when we should have been talking about the horse, that he had weak legs. It is built on a foundation of sand."
The FDA general counsel wrote a letter to Consumer Attorney, James Turner, Esq. responding to Mr. Turner's concern about the quality and validity of G.D. Searle's experiments. The FDA stated, "The Public Board of Inquiry on aspartame should provide a vehicle for definitive resolution, at least for those studies about which you are most concerned.
As will be discussed later, Dr. John Olney and James Turner, Esq. were not allowed to have the quality and validity of the G.D. Searle studies considered at the Public Board of Inquiry.
On December 13, 1978, UAREP submitted its results of their analysis of 12 of G.D. Searle's aspartame studies. UAREP stated in their report that "no discrepancies in any of the sponsor's reports that were of sufficient magnitude or nature that would compromise that data originally submitted." (Farber 1989, page 33) Remember, the Director of UAREP pointed out in an interview that their pathologists did not conduct a comprehensive review of the studies, they only looked at the animal tissues.
As it turns out, UAREP pathologists who examined the test results were discovered to have missed and withheld negative findings from the FDA. In some cases, they completely missed cancerous brain tumors when analyzing the slides. In addition, some of the slides that were to be examined by UAREP pathologists were missing even though they where supposed to have been kept under "FDA seal." (Olney 1987, page 6-7)
FDA Toxicologist Adrian Gross stated that the UAREP review "may well be interpreted as nothing short of a whitewash." (Farber 1989, page 114). Given that the UAREP review results were so biased in favor of G.D. Searle, one wonders why the FDA would allow a company being investigated for fraud to pay $500,000 and hire an outside entity to "validate" their studies.
Even though the UAREP report was biased, there were numerous instances in that report which demonstrated that G.D. Searle had not submitted even marginally accurate findings to the FDA of their pre-approval aspartame tests. For example, in one study, twelve animals actually had cancerous brain tumors, yet UAREP reported to the FDA that only three animals had such tumors.
In March of 1979, the FDA somehow concluded that G.D. Searle's aspartame studies could be accepted. They decide to convene the Public Board of Inquiry (PBOI) which was agreed to by Dr. John Olney and Attorney James Turner more than four years earlier (Federal Register 1979).
In April of 1979, the FDA outlined the specific questions which were to be addressed by the PBOI. The FDA limited the scope of the PBOI to (Federal Register 1981):
- Whether the ingestion of aspartame either alone or together with glutamate poses a risk of contributing to mental retardation, brain damage, or undesirable effects on neuroendocrine regulatory systems.
- Whether the ingestion of aspartame may induce brain neoplasms (tumors) in the rat.
- Based on answer to the above questions.
(i) Should aspartame be allowed for use in foods, or, instead should approval of aspartame be withdrawn?
(ii) If aspartame is allowed for use in foods, i.e., if its approval is not withdrawn, what conditions of use and labeling and label statements should be required, if any?
Dr. John Olney, G.D. Searle, and the FDA's Bureau of Foods were allowed to nominate scientists for the 3-person PBOI panel (Farber 1989, page 34, Federal Register 1981, page 38286).
It is important to note that the scope of the review was very limited in light of all of the various adverse reactions reported to the FDA. The PBOI also disallowed any discussion of the validity of the pre-approval experiments because it accepted the word of certain FDA officials that these experiments had been "validated." Finally, the PBOI was told not to consider aspartame in beverages, only in dry goods.
In June of 1979, the acting FDA Commissioner, Sherwin Gardner selected the 3-person Public Board of Inquiry. The panelists were Peter J. Lampert, M.D., Professor and Chairman, Department of Pathology, University of California (San Diego), Vernon R. Young, Ph.D., University of Nutritional Biochemistry, M.I.T., and Walle Nauta, M.D., Ph.D., Institute Professor, Department of Psychology and Brain Science