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The 1962 Amendments: Impact on Enforcement

Remarks delivered by Deborah Autor, J.D.,
Deputy FDA Commissioner for Global Regulatory Operations and Policy
at "Celebrating a Public Health Milestone"
White Oak Campus of the Food and Drug Administration
Simultaneous Webcast to FDA Employees
October 2, 2012

The Commissioner and others spoke eloquently about the great importance of the Kefauver-Harris Amendments.  I want to go into some of the details of what they have meant for FDA and its industry oversight.  

First, the thalidomide tragedy itself created a significant challenge for FDA field staff.  Over 1,200 U.S. physicians had been given thalidomide for testing but without a meaningful tracking system.

This led one FDA investigator to note, "I cannot help but have doubts about the adequacy and effectiveness of the [recall] procedures followed…since no formal letter was used, no material was returned, and…[there’s] no record or information as to how much material was destroyed…if any."

In response, on July 27, 1962, the FDA’s Bureau of Field Administration directed District Offices to find and remove from circulation all thalidomide stocks that were unaccounted for—by contacting each of the 1,200 plus physicians personally. 

In fact, the situation was so dire and complex that when asked a question about thalidomide in his press conference on August 1, 1962, President Kennedy himself urged all women around the country to check the family medicine chest to make sure the drug was turned over to the FDA. 

Implementing the efficacy requirement for drugs that were already on the market was also a massive undertaking for FDA.  Many of you are familiar with the Drug Efficacy Study Implementation, commonly known as DESI, that FDA undertook after the 1962 Amendments. 

The DESI program was intended to review all drugs with New Drug Applications marketed before 1962 and determine whether there was evidence of effectiveness for the drug’s labeled indications.  Those drugs had been approved for safety, but their efficacy had not been reviewed.

The DESI program demanded a great commitment from FDA staff for more than a decade—and required collaboration of FDA review divisions, compliance, investigators in the field, and countless others.

DESI evaluated over 3,000 separate products, and by 1984, the agency had completed the majority of its reviews.  Sixty percent of the over 16,000 reviewed therapeutic claims were considered effective.  But, notably, only 12 percent of the drug products approved before 1962 were found to be effective for ALL of their indications.  Over 1,000 of the products were removed from the market as lacking evidence of effectiveness for any indication. 

Other parts of the 1962 Amendments have also continued to have a major impact on FDA’s oversight of the industry.  One notable requirement relates to drug manufacturing.  Tragedies that pre-dated thalidomide made clear the need for enhancements in the quality and manufacturing of pharmaceutical products.

In 1941, because of poor manufacturing controls, sulfathiazole tablets were contaminated with phenobarbital—leading to nearly 300 deaths and injuries. This tragedy, coupled with the firm’s serious problems in attempting to recall the tablets, caused FDA to drastically revise manufacturing and quality controls, the beginning of what would later be called good manufacturing practices or GMPs.

Another significant case occurred in 1955, after Jonas Salk developed the polio vaccine.  Manufacturers quickly ramped up production to meet public demands for vaccination. 

But, one company failed to inactivate the virus completely in one lot during production.  That failure led to 94 inoculated patients developing polio, and 166 of their family members subsequently contracting the virus—ultimately leaving 192 of those patients paralyzed. 

Although the term "good manufacturing practices" had been used in essence for some time…in 1962, Congress broadened the statute to include the term current good manufacturing practices or cGMPs. 

The word "current" is important.  It means that as the science and art of drug manufacturing progress, industry needs to keep up and progress, too. 

In addition to cGMPs, the ‘62 Amendments included other significant requirements for industry oversight.  U.S. drug manufacturers now needed to register annually with the government and make their manufacturing records available; and FDA now was directed  to inspect U.S. drug manufacturing facilities at least once every two years.    

As Congress stated in its report in 1962, "drugs should not be on the market unless the FDA knows who is making them, and where they are being made, and is able to inspect the facilities in which they are being made."

Finally, the Kefauver–Harris Amendments also gave FDA a strong role in overseeing clinical research.  This happened, in part, due to thalidomide and the work of Dr. Kelsey, when investigations found that clinical studies involving this drug had not been conducted in a rigorous, scientific fashion. 

One physician who was testing the use of thalidomide in U.S. patients admitted he did not keep records of his use of the drug, and often transmitted any research findings by telephone or even during a round of golf.

Shortly after the 1963 Investigational New Drug Regulations were in place, a small investigative unit was formed to begin looking for "suspect" clinical investigators who could be conducting poor quality research. 

The unit, titled the Division of Scientific Investigations, was headed by Dr. Kelsey, and the nickname "Kelsey’s Kops" was born.  Later, this blossomed into an agency-wide program of clinical trial oversight.
So, how does it all look today? 

We continue our efforts to ensure that drugs are not on the market unless they have been proven safe and effective.  In part to enforce the Kefauver-Harris efficacy requirement, in 2006, FDA announced a new drug safety effort, the Unapproved Drugs Initiative, designed to remove unapproved drugs from the market through a risk-based enforcement program.  

To date, the Unapproved Drugs Initiative has taken a variety of enforcement actions, including 20 drug class actions that have impacted over 1,200 products and 200 firms.  Perhaps even more importantly, because of the Initiative more than 123 drug products that were previously unapproved have now obtained FDA approval.

Just this year, under the Food and Drug Administration Safety and Innovation Act or FDASIA, drug registration requirements have been strengthened and clarified, and the definition of "current good manufacturing practices" has been amended to explicitly include quality systems and risk management.

And today, our drugs are made all over the world—80 percent of our active pharmaceutical ingredient manufacturers are outside the U.S., and we import 40 percent of our finished drugs.  Drug quality is now a worldwide concept, and we increasingly work through global collaborations, such as the International Conference on Harmonization and the Pharmaceutical Inspection Cooperation Scheme, to converge our cGMP requirements with standards set around the world, fostering a culture of quality worldwide, while also creating efficiencies for regulators and industry.

We continue to inspect drug facilities.  In 2011, FDA conducted nearly 3,000 drug inspections—a quarter of them outside of the U.S.  And again, the Kefauver-Harris two year inspectional requirement was changed this year by FDASIA.  The law now recognizes that FDA must oversee all drug manufacturers, whether they are domestic or abroad, and do so on a schedule based on risk, and not the calendar.  

As for clinical trials, there too we are collaborating with our international counterparts to protect patients globally.  This includes cultivating novel clinical trial designs, developing innovative tools to aid in inspecting studies around the world, and fostering a quality systems approach that promotes innovation in research while ensuring high quality data for decisions on drug approval. 

In short, the world continues to evolve, but our modern system continues to rest squarely on the foundation put in place by the Kefauver-Harris Amendments.  That law created a modern drug regulatory system…which is integral to today’s efforts to address challenges and protect patients in a complex, globalized regulatory environment.