Nidhi Tripathi, Kate Davis, Catherine Bodine, and Daniel K. Benjamin Jr.
Since early civilizations, people have been concerned about the quality, safety, and integrity of foods and medicines. Curiosity about these matters began thousands of years ago.
In the Bible’s Old Testament, the first chapter of the Book of Daniel describes a clinical trial. After conquering Israel, Nebuchadnezzar, the king of Babylon, ordered that several Jewish youths be brought to his palace to serve for 3 years. The children would be fed and taught just like the king’s own children. Among the youths was Daniel, who did not wish to defy Jewish law by eating the king’s meat or drinking his wine. Daniel asked that the Jewish youth be allowed to eat peas and beans (“pulse”) and to drink water instead of wine. Melzar, the eunuch assigned to watch over the youth, was hesitant, fearing Nebuchadnezzr’s wrath should Daniel and the other youth become ill. Daniel suggested a 10-day experiment of feeding the Jewish youth pulse and water, while the king’s servants continued the rich meats and wine as prescribed by the king.
The result: Daniel 1:15–1:16, King James Version:
And at the end of ten days their countenances appeared fairer and fatter in flesh than all the children which did eat the portion of the king’s meat.
Thus Melzar took away the portion of their meat, and the wine that they should drink; and gave them pulse.
The first known English food law was enacted in 1202, when King John of England proclaimed the Assize of Bread, a law prohibiting the adulteration of bread with ingredients such as ground peas or beans (1). One of the earliest food and drug laws in the United States was enacted in 1785, when the Commonwealth of Massachusetts passed the first general food adulteration law regulating food quality, quantity, and branding.
Since these early times, many events, often accompanied by tragic outcomes, have raised additional concerns related to food and drug safety.
As we progressed toward more modern times, clinical trials began using specific experimental designs and collected information in numbers rather than in statements such as “looked healthier and better nourished.”
One of the earliest examples of an experimental design can be traced to 1767 and William Watson, who was the physician for the Hospital for the Maintenance and Education of Exposed and Deserted Children in London, England. At that time, the leading cause of death among children in London was smallpox, and the governors of the hospital ordered that all children who were not already immune to smallpox be inoculated. Although inoculation was already an accepted practice, Watson was curious about the benefit of routinely using mercury as a concomitant treatment with the inoculum.
In October 1767, Watson performed his first experiment, giving 31 children the same inoculum and then dividing them into three similar groups:
• 10 children (5 boys and 5 girls) received a mixture of mercury and jalap (a laxative)
• 10 children (5 boys and 5 girls) received an infusion of senna and syrup of roses (a mild laxative)
• 11 boys received no concomitant medicines
Watson understood that he would need to clearly show a lack of efficacy in the use of mercury to convince others to abandon its use. Therefore, he made every effort to create similar groups for comparison. He not only included groups of children of similar ages and both sexes but also demanded that all of the children eat the same diet, wear similar clothes, play in the same fields, and sleep in the same dormitories. In each experiment, the children were inoculated at the same time and place with the same material. Watson understood that “it was proper also to be informed of what nature unassisted, not to say undisturbed, would do for herself” (2). His introduction of an untreated control group, the 11 boys who received no concomitant medicines, was his way of determining the outcome when nature was “unassisted.” Watson’s method allowed him to compare the results in the three groups (3).
Also during the mid-18th century, James Lind was investigating the cause of and cure for scurvy among seamen. In at least two respects, Lind’s Treatise of the Scurvy (4) is a good illustration of the basis for mid-18th century judgment and decision making, in that it quotes the contributions of others at length, and its therapeutic recommendations had little impact (5).
When Lind began to read the literature on scurvy, he realized that the only existing descriptions of the disease were written either by seamen who were not doctors or by doctors who had never been to sea. Lind felt that this was one of the reasons why there was so much confusion about the diagnosis, prevention, and cure of the disease.
Although he was a physician, Lind’s experiment was not based on pathophysiological theory. He gave no reason for his choice of possible treatments—vinegar, cider, elixir of vitriol, seawater, and lemons and oranges—each of which was given to two seamen. His trial succeeded because one of the treatments contained vitamin C. Lind knew how to perform a comparative experiment and how to control well for time and environment, but he knew perhaps less well which experiment he should do. Had his experiment been based on theory, his work might have been more likely to receive credit with the medical establishment rather than take more than 40 years to be put into practice.
The US Food and Drug Administration (FDA), an agency of the Department of Health and Human Services, is charged with the regulation and supervision of most food products, human and animal drugs, biologics, medical devices, cosmetics, and animal feed.
Efforts to protect consumers were first made in the 1800s as early scientific studies continued to develop products for use in humans (Table 1–1). In the 1820s, the first US Pharmacopeia was produced, which set standards for the strength, purity, quality, and consistency of drugs (6). In 1848, Lewis Caleb Beck was appointed to the Patent Office to carry out chemical analyses of agricultural products; many view his appointment as a crucial early step in the development of what is now the FDA. Shortly, thereafter, the Drug Importation Act was passed in response to the deaths of American soldiers from adulterated quinine. This act charged US Customs officers with inspecting and prohibiting the entry of adulterated drugs from overseas.
TABLE 1–1
Timeline of notable events (6)
In 1862, Charles M. Wetherill was appointed chemist for the new Department of Agriculture. This was the beginning of the Bureau of Chemistry, the predecessor to the FDA. Investigations of food adulteration conducted by the Department of Agriculture became fodder for the eventual creation of a food and drug regulatory body. It was not until the United States and Europe suffered a number of tragedies, however, that an official governing board, which eventually became the modern-day FDA, was formed.
The late 19th century marked the blooming of international biologics research, leading to the development of new tools for the treatment and prevention of disease (7). In Germany, Robert Koch discovered and isolated the pathogens that cause anthrax, cholera, tuberculosis, and rabies; Louis Pasteur developed a vaccine to protect fowl from cholera in France; and Americans Theobald Smith and Edmund Salmon created heat-killed vaccines to prevent hog cholera.
Soon immunological tools were developed for use in humans. Emil von Behring and Shibasaburo Kitasato, both working in Koch’s lab, discovered how to produce and isolate diphtherial and tetanus antitoxin using animal models. The antitoxins were able to both cure and prevent the recurrence of these deadly diseases. Diphtherial antitoxin was tested in human patients in 1891, and the Hoechst pharmaceutical company began commercial production soon thereafter. Serum antitoxin therapy drastically reduced the mortality attributed to diphtheria in Europe, and the Americans took note.
In the United States, diphtherial antitoxin was first produced in the public sector by the Hygienic Laboratory in Washington, DC and the Bacteriological Laboratory of the New York City Health Department. In both instances, horses were immunized to produce large quantities of serum. The private sector quickly developed the expertise necessary to mass-produce serum and vaccines and administer them with sterile syringes. Despite some discussion about the need for regulation and quality control of these biologic products, the private sector operated without oversight.
Tragedy struck in 1901. A 5-year-old girl in St. Louis, Missouri, died from tetanus after being given diphtheria antitoxin serum. Following her death, municipal officials traced the serum to the horse from which it had been produced. Much to their surprise and concern, they learned that the horse had been destroyed after it had contracted tetanus. Rather than discarding the serum isolated from this animal, company officials continued to distribute it to the community; 12 more children died of tetanus in St. Louis. Another 9 children died in New Jersey due to a contaminated smallpox vaccine soon thereafter.
These tragedies prompted Congress to pass the Biologics Control Act of 1902, under which manufacturers were required to be licensed annually to produce and sell vaccines, serums, and antitoxins. Facilities were subject to inspection and could be shut down for noncompliance with regulations. Biologic products were required to be clearly labeled with the product name and expiration date, and a qualified scientist had to oversee production. The 1944 Public Health Service Act extended licensing requirements to biologic products in addition to manufacturers.
The adulteration and misbranding of foods and drugs was commonplace at the end of the 19th century (8,9). When Harvey Washington Wiley became the chief chemist in the Division of Chemistry in 1883, he spearheaded the systematic evaluation of chemical preservatives and dyes used in food. A 10-part study entitled Foods and Food Adulterants, published from 1887 to 1902, outlined concerns about the impact of chemical preservatives on health. In these studies, preservatives were given to healthy volunteers in increasing amounts, and the responses were observed. The outrage generated by these studies, in addition to revelations about market conditions by journalists such as Samuel Hopkins Adams and novelists such as Upton Sinclair (The Jungle), were fuel for the passage of the 1906 Pure Food and Drugs Act.
The Pure Food and Drugs Act, signed into law by President Theodore Roosevelt, prohibited interstate commerce of misbranded or adulterated food, drugs, and drinks at the price of product confiscation or prosecution of the responsible parties. Manufacturers were required to accurately label the contents and dosage of drugs that varied from forms defined in the US Pharmacopoeia and the National Formulary. The act prohibited the adulteration and/or dilution of foods with any substance that could pose a health hazard, and the Bureau of Chemistry was charged with the responsibility of administering these regulations.
The first major test of the legislation came in 1910, when the government seized an ineffective product called Johnson’s Mild Combination Treatment for Cancer (10). The Supreme Court ruled in U.S. v. Johnson that false claims of effectiveness were not within the purview of the Food and Drugs Act. This loophole was closed in 1912 with the Sherley Amendment, which prohibited labeling with false therapeutic claims to defraud the purchaser. However, the burden of proof that the company intended to defraud the consumer still lay with the government, a task that proved difficult. Of note, the act did not require approval of drugs before marketing, simply truth in labeling.
The Bureau of Chemistry became the Food, Drug, and Insecticide Administration in July 1927, and the FDA in 1931.
Sulfanilamide was an antibiotic that had successfully and safely treated streptococcal infections for some time (11). Unfortunately, the available pill and powder formulations were not palatable, especially for children. In 1937, the S.E. Massengill Company in Bristol, Tennessee, developed a raspberry-flavored liquid formulation that was distributed across the country. The end product, Elixir of Sulfanilamide, caused the painful deaths of 107 people, mostly children. Although an elixir is an alcohol-based solution, the product sold by Massengill was dissolved in diethylene glycol, a toxic analog of antifreeze. The new formulation had not been tested for toxicity before being widely distributed, so its lethality was unknown.
After learning of these deaths, FDA investigators approached headquarters of the company and discovered that officials had already learned of the toxic effects of their drug. The company had contacted more than 1,000 salesmen, pharmacists, and doctors requesting the return of their product but had conveyed neither a sense of urgency nor information about the toxicity of the solution. The FDA was able to recall the drug from the market, not because of its lethality but because it was incorrectly labeled as an elixir. If not for this technicality, the FDA would have been powerless to act, and many more might have died.
Once again tragedy accelerated legislation. Until this time, there were no requirements to show the safety of a product before it was brought to market. Legislation updating the flawed 1906 Pure Food and Drugs Act, which had been stalled in Congress for 5 years, passed in 1938. Signed into law by President Franklin D. Roosevelt, the Food, Drug, and Cosmetic Act most notably required manufacturers to submit evidence of drug safety to the FDA before the drug could go to market (12). This marked the birth of the new drug application (NDA). Following an NDA submission, the FDA had 2 months to approve, reject, or request additional information before approval was automatically granted. The act further irrefutably prohibited false therapeutic claims, required that drugs be labeled with instructions for safe use, and extended consumer protection to medical devices and cosmetics. The 1951 Durham–Humphrey Amendment required that certain drugs be labeled for sale by prescription only (13).
Despite the dissemination of the Nuremberg Code outlining ethical practices in human research, in the 1950s and 1960s drug manufacturers still commonly sent doctors unapproved drugs for informal testing on patients without their consent (14). (There was no requirement that the FDA be informed when testing a new drug in humans.) This practice allowed more than 20,000 Americans, including more than 3,000 women of childbearing age and about 200 pregnant women, to be exposed to a drug called thalidomide despite a lack of marketing approval (15).
Thalidomide was manufactured in Germany and marketed as a sleeping aid and antiemetic for morning sickness. It was sold over the counter in Germany in 1957 and throughout Europe by 1960, with the claim that it was completely safe.
So as to introduce thalidomide to the American market, its manufacturer (Chemie Grünenthal) submitted safety studies to the FDA. An FDA medical officer, Frances Oldham Kelsey, was not satisfied by the safety or pharmacokinetic data submitted. Only a few low-quality studies had been performed in the United States, and there were no adequate data on the long-term effects of the drug. Case reports published in the British Medical Journal suggesting that peripheral neuropathy developed after chronic thalidomide therapy gave Dr. Kelsey pause. She was particularly concerned with the lack of information about whether the drug could cross the placenta and affect the developing fetus. Approval of the drug for marketing in the United States was stalled because of her misgivings.
Dr. Kelsey’s suspicions proved to be correct: more than 10,000 infants in Europe and Africa were born with severe birth defects, most commonly phocomelia—the shortening or absence of limbs. Despite the fact that more than 1,000 physicians were using thalidomide in informal “clinical trials,” this tragedy was largely averted in the United States due to Dr. Kelsey’s persistence. The narrowly averted thalidomide disaster in the United States led to substantial drug development reform.
The 1962 Kefauver–Harris Amendment led to sweeping reform of the FDA. It required for the first time that manufacturers provide proof of efficacy through adequate and well-controlled trials before marketing a drug. More stringent safety standards were to be enforced, and manufacturers were now required to report adverse events to the FDA. The act also defined ethical standards for the conduct of clinical trials, for example, the requirement for informed consent by the participants. Finally, the FDA now had to specifically approve the marketing application for each drug, and manufacturers were required to disclose the risks and benefits of prescription products to physicians.
Since the passage of the Kefauver–Harris Amendment, the FDA has been empowered to ensure the safe and efficacious use of drugs in the United States; new drugs must be studied in adequate and well-controlled trials that ultimately form the basis of labels and package inserts detailing safety, efficacy, and directions for use.
The irony of drug development legislation has been that although reforms were spurred largely by tragedies in children, the resulting reform efforts failed to protect children. Despite bearing the brunt of the tragedies that catalyzed the development of regulations, children were excluded from trials that allowed drugs to be brought to market.
By the 1990s, fewer than 15% of drug labels contained information about pediatric dosing, safety, or efficacy. As a result, pediatricians were forced to use these drugs “off-label” and to treat each child as an experiment with a sample size (n) of 1. Neonates and infants were most often neglected in clinical trials because the study of drugs in this population is both technically and ethically challenging. However, the extrapolation of adult or older pediatric safety and dosing information to very young patients is ill advised because of the variable and developing physiology of children. Infants have been victims of unforeseen adverse events, including the development of kernicterus in premature infants treated with prophylactic sulfisoxazole and “gray baby syndrome” resulting from prophylactic chloramphenicol use in the 1950s (16).
The 1997 Food and Drug Administration Modernization Act (FDAMA) provided a financial incentive for pharmaceutical companies to study on-patent drugs in children. It granted an additional 6 months of marketing exclusivity to manufacturers who carried out studies in children in response to an FDA-issued written request. The exclusivity provision was extended under the 2002 Best Pharmaceuticals for Children Act (BPCA) and subsequently renewed in 2007. The BPCA further established a publicly funded mechanism for the study of generic off-patent drugs in children. The Pediatric Research Equity Act (PREA) of 2003 gave the FDA the authority to require drug sponsors to conduct clinical research into pediatric applications of new drugs that may reasonably be used in this population.
FDAMA has successfully stimulated pediatric drug research. Since its enactment in 1997, more than 350 written requests have been issued concerning about 900 studies (17), and there have been 427 labeling changes as of March 2012, mostly attributable to the BPCA or PREA (18). We have learned that simple extrapolation of pharmacokinetic data from adults to children is inadequate, often leading to failed efficacy trials in children not because the drugs are ineffective but because they are not given in appropriate dosages or formulations (19,20).
The increased number of pediatric trials has not resulted in a proportional increase in the number of publications (21,22). The results of only half the studies conducted for additional marketing exclusivity have been published in peer-reviewed journals; those with positive labeling changes are more likely to be published (21). Of particular concern is the small number of safety trials that have been published and the presentation of safety data in a way that is more favorable than the data submitted to the FDA (22). Without widespread publication of trial results, the FDA’s review of data produced by the manufacturer in safety, pharmacokinetic, and efficacy trials is the strongest facet of consumer protection and physician guidance.
From its humble beginnings as the Department of Agriculture and the 1906 Pure Food and Drugs Act, the modern-day FDA has evolved into an important regulatory body whose jurisdiction encompasses most human and animal food products, drugs, biologics, medical devices, and cosmetics (8). Today, the FDA has a multibillion-dollar budget that it uses to regulate and ensure the safety and efficacy of new products and drugs and to supervise production of $1 trillion worth of products annually.
1. US Food and Drug Administration. Milestones in U.S. Food and Drug Law History. http://www.fda.gov/AboutFDA/WhatWeDo/History/Milestones/default.htm. Accessed June 27, 2012.
2. Watson W. An Account of a Series of Experiments, Instituted with a View of Ascertaining the Most Successful Method of Inoculating the Small-Pox. London: J. Nourse; 1768.
3. Boylston AW. Clinical investigation of smallpox in 1767. N Engl J Med. 2002;346(17):1326-1328.
4. Lind J. A Treatise of the Scurvy. Edinburgh: Sands, Murray & Cochran; 1753.
5. Tröhler U. Lind and scurvy: 1747 to 1795. J R Soc Med. 2005;98(11): 519-522.
6. US Food and Drug Administration. Milestones in U.S. Food and Drug Law History—Significant Dates in U.S. Food and Drug Law History. 2010. http://www.fda.gov/AboutFDA/WhatWeDo/History/Milestones/ucm128305.htm. Accessed April 4, 2012.
7. White Junod S. Selections from FDLI Update Series on FDA History—Biologics Centennial: 100 Years of Biologics Regulation. 2002. http://www.fda.gov/aboutfda/whatwedo/history/productregulation/selectionsfromfdliupdateseriesonfdahistory/ucm091754.htm. Accessed April 4, 2012.
8. Swann JP. FDA’s Origin & Functions—FDA’s Origin. 2009. http://www.fda.gov/AboutFDA/WhatWeDo/History/Origin/ucm124403.htm. Accessed April 4, 2012.
9. US Food and Drug Administration. FDA’s Origin & Functions—FDA History—Part I. 2009. http://www.fda.gov/AboutFDA/WhatWeDo/History/Origin/ucm054819.htm. Accessed April 4, 2012.
10. Meadows M. Promoting Safe and Effective Drugs for 100 Years. http://www.fda.gov/AboutFDA/WhatWeDo/History/ProductRegulation/PromotingSafeandEffectiveDrugsfor100Years/default.htm. Accessed April 4, 2012.
11. Ballentine C. Sulfanilamide Disaster. 1981. http://www.fda.gov/AboutFDA/WhatWeDo/History/ProductRegulation/SulfanilamideDisaster/default.htm. Accessed April 4, 2012.
12. US Food and Drug Administration. Summary of NDA Approvals & Receipts, 1938 to the Present. 2011. http://www.fda.gov/AboutFDA/WhatWeDo/History/ProductRegulation/SummaryofNDAApprovalsReceipts1938tothepresent/default.htm. Accessed April 4, 2012.
13. US Food and Drug Administration. FDA’s Origin & Functions—FDA History—Part III. 2009. http://www.fda.gov/AboutFDA/WhatWeDo/History/Origin/ucm055118.htm. Accessed April 4, 2012.
14. Liu MB, Davis K. A Clinical Trials Manual from the Duke Clinical Research Institute: Lessons from a Horse Named Jim. 2nd ed. Hoboken, NJ: Wiley-Blackwell; 2010.
15. Fintel B, Samaras AT, Carias E. The Thalidomide Tragedy: Lessons for Drug Safety and Regulation & pipe; Science in Society. 2009. http://scienceinsociety.northwestern.edu/content/articles/2009/research-digest/thalidomide/title-tba. Accessed April 4, 2012.
16. Robertson AF. Reflections on errors in neonatology: II. The “Heroic” years, 1950 to 1970. J Perinatol. 2003; 23(2):154-161.
17. US Food and Drug Administration C for DE and R. Development Resources—Breakdown of Requested Studies Report. 2009. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm050001.htm. Accessed April 4, 2012.
18. US Food and Drug Administration. New Pediatric Labeling Information Database. http://www.accessdata.fda.gov/scripts/sda/sdNavigation.cfm?sd=labelingdatabase. Accessed April 4, 2012.
19. Dunne J, et al. Extrapolation of adult data and other data in pediatric drug-development programs. Pediatrics. 2011; 128(5):e1242-e1249.
20. Benjamin DK Jr, et al. Pediatric antihypertensive trial failures: analysis of end points and dose range. Hypertension. 2008;51(4):834-840.
21. Benjamin DK Jr, et al. Peer-reviewed publication of clinical trials completed for pediatric exclusivity. JAMA. 2006;296(10):1266-1273.
22. Benjamin DK Jr, et al. Safety and transparency of pediatric drug trials. Arch Pediatr Adolesc Med. 2009;163(12): 1080-1086.
