Tuesday, August 11, 2015

Uncertain Health in an Insecure World – 52


“When the whole world is silent, even one voice becomes powerful.”
Malala Yousafzai (2014 Nobel Peace Prize)

When Frances Kathleen Oldham applied for a pharmacology lab position in 1935, University of Chicago Professor Eugene Geiling offered “Mr. Oldham” the job without an interview. Her McGill University training was top notch, and she was encouraged by her mentor to accept the offer. Last week, “Miss Oldham” (below), died in London Ontario with her family beside her at age 101.

She lived a long life, a moral life, mostly in obscurity.

As the U.S. Food & Drug Administration (FDA) medical officer in the 1960's, Dr. Frances Kathleen Kelsey (since married) received the William S. Merrell Company of Cincinnati request to market thalidomide in the U.S. The drug, called Kevadon™, was portrayed as a miracle cure for morning sickness of pregnancy, an indication for which it had been approved in nearly fifty countries since its introduction by Germany’s Chemie Grünenthal in 1957. On this basis, Merrell Co. expected a routine review and rubber stamp approval.

Dr. Kelsey, a serious scientist, had serious reservations.

Her opposition to thalidomide made her a target of company lobbying and complaints to her FDA superiors. Probing questions about the drug’s safety delayed FDA actions until 1961, when a German researcher found a link to serious newborn lung and limb malformation defects (phocomelia, see below), and in utero deaths. Over 10,000 cases were reported worldwide, mostly in Europe, Britain, Canada and the Middle East, of which only 50% survived beyond childhood. 

For her courage in defense of human health under pharmaceutical company fire, in 1962 President John F. Kennedy presented Dr. Kelsey with the highest U.S. award for civilian service at a White House ceremony (below). The U.S. Congress passed legislation, signed by President Kennedy, requiring drug makers to prove that new drugs were safe and effective before marketing. Dr. Kelsey was put in charge of FDA's new drug safety branch in 1962; she had a distinguished 45 year career.

Thanks to Dr. Kelsey, thousands lived and avoided suffering.

Remarkably, thalidomide is still sold globally by Celgene as an immune-modulator drug for the treatment of non-pregnant patients with multiple myeloma (FDA approved in 2006, Australia TGA approved in 2009, EU EMA approved in 2008), HIV-associated Kaposi sarcoma & wasting, Crohn’s disease, and skin complications of leprosy (FDA approved in 1998, TGA approved in 2009).  Modern immuno-therapies are likely to signal an end to thalidomide therapy in the developed world by 2020, but its use in the developing world will continue. 

Dr. Kelsey’s work gave birth to the modern era of pharmaco-vigilance (PV). 

PV is defined by the World Health Organization (WHO) as the pharmacologic science and activities related to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problems. Over 100 countries have committed to WHO’s International Drug Monitoring Programme, contributing information to an international database. As specified by the EU definition of PV, the emphasis is monitoring and related actions to mitigate the drug’s potential for post-marketing adverse impact on public health.  Such pro-active risk management includes post-release regulatory actions (i.e., additional labeling) by the FDA, European Medicines Agency (EMA), etc.

Given the dire consequences of laxity, a large PV industry sector has naturally emerged.

Others responsible for effective PV include patients, healthcare providers, pharmaceutical companies and drug importers. Large pharma companies and medical device makers are required to carry out post-marketing surveillance (PMS; a.k.a. Phase-4 trials) for years following regulatory approval. FDA’s Adverse Event Reporting System (FAERS) is a central database designed to monitor and analyze reported adverse events and poisonings. FDA’s MedWatch Program website is designed for healthcare professionals and the public to report reactions to drugs & devices, which are entered into the FAERS database.

Medication distributors have established subsidiaries (i.e., Express Scripts’ UBC) dedicated to PV functions. Clinical research organizations like Parexel include PV in their menu of CRO services. Specialty firms (i.e., Clinquest, Prosar) perform post-marketing PV for drugs and devices throughout product life cycles. The PV sector now sponsors international journals, professional societies and scientific sessions.

Last week’s FDA approval of a highly porous anti-epilepsy drug delivery system made using 3D printing (Aprecia’s Spritam, above) is a good example of the high tech and biotechnology that regulatory agencies must now evaluate before and be vigilant about long after marketing begins. 

Fifty-three years later after being honored by JFK, on the day before her death, Dr. Kelsey received the Order of Canada. In March of 2015, 126 surviving Canadian thalidomide victims received $125,000 each from the Canadian government. Daughter Christine Kelsey reflected back on “Frankie’s” early life in a 2010 New York Times article, saying “When a woman took a job in those days, she was made to feel as if she was depriving a man of the ability to support his wife and child.”

Thanks to “Frankie” and others, women have come a long way in science and medicine.

While important and hard, there is little heroic about pharmaco-vigilance.

We in the Square profess that personal heroism is lonely, often occurring before the organized world requires it. 

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