Food and Drug Act and its Limitations_final2

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SULFANILAMIDE & THALIDOMIDE VIOLATIONS AND CORRESPONDENT LAWS Presented By : - Shalini shukla  Prajakta Nerurkar  SHweta DoYALE Uthara Iyer  sheetal HELEKAR Batch-CR-12 10.07.2010

Reactionary Regulatory Guidance : 

Reactionary Regulatory Guidance Pure Food and Drug Act - 1906 Food, Drug, and Cosmetic Act - 1938 Elixir sulfanilamide tragedy Required pre-market safety Kefauver-Harris Amendments - 1962 Thalidomide Clinical studies supported by animal testing

Food and Drug Act -1906 : 

Food and Drug Act -1906 The 1906 regulations were enforced by the Bureau of Chemistry in the Department of Agriculture. The 1906 Pure Food and Drugs Act. Also known as the Wiley Act. This landmark act was passed during the progressive era of President Theodore Roosevelt at the urging of Dr. Harvey W. Wiley, the chief chemist at the Department of Agriculture. Department of Agriculture

Provisions Under The Wiley Act : 

Provisions Under The Wiley Act The basis of the law rested on the regulation of product labeling. Drugs could not be sold in any other condition unless the specific variations from the applicable standards were plainly stated on the label. (United States Pharmacopoeia, National Formulary) Foods - The law prohibited the addition of any ingredients that would substitute for the food, conceal damage, pose a health hazard, or constitute a filthy or decomposed substance. Dr. Harvey W. Wiley

Provisions (Continued) : 

Provisions (Continued) If the manufacturer opted to list the weight or measure of a food, this had to be done accurately. MISBRANDING: The food or drug label could not be false or misleading in any particular, and the presence and amount of eleven dangerous ingredients, including alcohol, heroin, and cocaine, had to be listed.


LIMITATIONS Under the 1906 law, the agency was primarily a policing organization that responded to violations of food and drug regulations after they occurred. In cases of suspected adulteration, drugs were tested for strength and purity. The law did not address the testing of new drugs.

Gerard Domagk (1932) : 

Gerard Domagk (1932) Prontosil rubrum (red dye stuff) protected mice from lethal doses of Staphylococcus and hemolytic Streptococcus derivative of sulfanilamide (1908) Daughter with severe streptococcal infection (sore throat) Prontosil® -> complete recovery Nobel Prize in Physiology or Medicine (1939)

Sulfanilamide-The Wonder Drug : 

Sulfanilamide-The Wonder Drug Prontosil p-aminobenzenesulfonamide (Sulfanilamide) In January 1937, sulfanilamide was endorsed for streptococcal infections. Sulfanilamide was endorsed by AMA & developed Squibb Merck Winthrop Eli Lilly Park-Davis.

S.E. Massengill Company of Bristol : 

S.E. Massengill Company of Bristol Founded by Samuel E. Massengill (1871-1946), also began to produce sulfanilamide. Sulfanilamide was synthesized in capsule and tablets forms till then and there was an increasing demand for the liquid form of the drug. Harold Cole Watkins, the chief chemist of the company introduced the idea of using diethylene glycol to make a liquid formulation of sulfanilamide. This is where the toxic incident occurred. Diethylene glycol was an anti freeze and there was a paucity of scientific data on the clinical effect of this solvent.


ELIXIR SULFANILAMIDE Eventually – raspberry-tasting pink preparation 10% sulfanilamide 72% diethylene glycol 16% water Flavor, raspberry extract, saccharine, amaranth and caramel Labelled as “Elixir sulfanilamide”

Massengill’s Control laboratory tested preparation for: : 

Massengill’s Control laboratory tested preparation for: Appearance Flavor Fragrance No laws regulating pre-market approval


DISTRIBUTION A total of 1304 shipments were distributed across the U.S. One of the major delivery points was Tulsa, Oklahoma. 353 patients received Elixir Sulfanilamide over a 4- week period

2nd October 1937 : 

2nd October 1937 Editorial in JAMA “Warning against overzealous embrace of sulfanilamide” Adverse reactions Dermatitis Photosensitivity Granulocytopenia Hemolytic Anemia Sulfanilamide—a warning (Editorial). JAMA. 1937; 109:1128

Slide 14: 

Reports of deaths from Tulsa reached AMA AMA acquired exact composition of Sulfanilamide from Massengill. AMA reported that Antidote to Sulfanilamide was unavailable at the time. FDA intervenes Walter Campbell, the chief of the FDA orders thorough investigation into the incident FDA confiscates 228/240 gallons of the drug.

FDA Acts : 

FDA Acts FDA intervened due to misbranding not due to deaths Marketed as an elixir but did NOT contain ethanol. Anything called an elixir must contain ethanol

Congress to the Rescue : 

Congress to the Rescue Senator Royal Copeland – Senator Bill was introduced On Dec 1 1937 Six months later, on 25th June, President Franklin Roosevelt signed the 1938 Federal Food, Drug and Cosmetic Act into law Senator Royal Copeland President Franklin Roosevelt

1938 Food Drug and Cosmetic Act : 

1938 Food Drug and Cosmetic Act (1) Requirement of New Drug Application (NDA) report-Drug safety before the interstate shipment of any new pharmaceutical agent. (2) Banned - Dangerous drugs (for example, radium water) False and misleading labeling. (3) Formula must be disclosed (4) Directions for use and precautions on prescription

NDA-New Drug Application : 

NDA-New Drug Application An application for approval by the Food and Drug Administration of a new pharmaceutical compound for introduction to the market. The data gathered during the animal studies and human clinical trials of an Investigational New Drug become part of the NDA.

Goals of NDA : 

Goals of NDA To ensure whether The drug is safe and effective in its proposed use, The benefits of drug outweigh its risk, The package insert is appropriate, The manufacturing methods & controls used for quality assurance preserve drug’s identity, strength, quality, and purity.

Conclusion : 

Conclusion The legacy of the Elixir Sulfanilamide tragedy…. The successful passage of the 1938 Federal Food, Drug, and Cosmetic Act SHOW DRUG SAFETY BEFORE PUBLIC SALE AND DISTRIBUTION. Steps to prevent Adulteration and ensure Safety and Quality of ingredients.




CHEMISTRY Thalidomide (α-phthalimidoglutarimide) Synthesized by Chemie Grünenthal in West Germany in 1954 R-thalidomide (d) S-thalidomide (l)


GLOBAL EFFECT Thalidomide was present in at least 46 countries under many different brand names. Some are listed below

Thalidomide, was hailed as a "wonder drug" that provided a "safe, sound sleep". : 

Thalidomide, was hailed as a "wonder drug" that provided a "safe, sound sleep".

It was also seen that Thalidomide cured morning sickness in Pregnant Women : 

It was also seen that Thalidomide cured morning sickness in Pregnant Women

Thalidomide Tragedy : 

Thalidomide Tragedy Thalidomide was a catastrophic drug with tragic side effects. Resulted in miscarriages, stillbirths and birth malformations.

Mode Of Action : 

Mode Of Action Thalidomide enters blood stream Crosses placenta interferes with growth patterns in foetus

Side effects of Thalidomide : 

Side effects of Thalidomide For those babies who survived, birth defects included: Deafness, Blindness, Disfigurement, Cleft palate, Many other internal disabilities (congenital heart disease, microphthalmos and coloboma, intestinal atresis, renal malformations, abnormal pinnae, and facial naevus. )

The most renowned is Pharcomelia, the name given to the flipper-like limbs which appeared on the children. : 

The most renowned is Pharcomelia, the name given to the flipper-like limbs which appeared on the children.


THALIDOMIDE IN UNITED STATES US License obtained in 1958, but marketing was delayed for 20 months by clinical trial safety testing. The impact in the United States was minimized when pharmacologist and M.D. Frances Oldham Kelsey refused FDA approval for marketing Kevadon® in the U.S.

Slide 32: 

1962: FDA inspector, Frances Oldham Kelsey receives the Distinguished Federal Civilian Service Award from President John F. Kennedy for blocking sale of Thalidomide in the United States

Kefauver–Harris Amendment : 

Kefauver–Harris Amendment The Bill was introduced by: U.S. Senator Estes Kefauver, of Tennessee -Anti-Trust and Monopoly Subcommittee & U.S. Representative Oren Harris, of Arkansas. -Federal Judge The law was signed by President John F. Kennedy on October 10, 1962.

Slide 34: 

Also called “the Drug Efficacy Amendment” Signing of the Kefauver-Harris Amendment

1962 Kefauver-Harris Amendment : 

1962 Kefauver-Harris Amendment Proof-of-efficacy requirement, that was not present before Report Adverse Drug Events to FDA Required Informed Consent in the Clinical Testing Process Mandated standard “Good Manufacturing Practices” Transferred Jurisdiction over Prescription Drug Advertising to FDA from Federal Trades Commission (FTC)

1962 Kefauver-Harris Amendment : 

1962 Kefauver-Harris Amendment Required that advertising provide complete information on risks and benefits Drug manufacturers were required to register annually The Drug Efficacy Study Implementation was begun Mandated inspection of Drug Manufacturers every two years IND exemption

Definition of IND : 

Definition of IND IND means a new drug or biological drug that is used in a clinical investigation. WHY IND APPLICATION? Current Federal law requires that a drug be the subject of an approved marketing application before it is transported or distributed across state lines. Because a sponsor will probably want to ship the investigational drug to clinical investigators in many states, it must seek an exemption from that legal requirement. The IND is the means through which the sponsor technically obtains this exemption from the FDA.


IND APPLICATION 21 CFR part 312 Provides procedures for use of investigational new drugs Registration Listing Interstate distribution Labeling GMPs

Thalidomide effects and victims : 

Thalidomide effects and victims


THALIDOMIDE TODAY Thalidomide has now been re-introduced as a treatment for leprosy and FDA approved it in 1998.


THALIDOMIDE TODAY Ongoing studies for AIDS Rheumatoid arthritis Inflammatory bowel diseases Some Cancers like Multiple Myeloma Thalidomide has now being used for several diseases

Bibliography : 




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