Send in the Orphans - A brief history of informed consent!

Most of us accept informed consent as routine and automatic. But given our track record in looking out for others outside our own intimate group, it serves us well to conduct a reality check on occasion.

Throughout history we can find numerous instances where the people in control have preyed on the weak or the powerless. Many people know the stories of the Nazi atrocities during the 1930s and 1940s and the experiments the Japanese conducted on the Allied POWs during World War II, but the use of uninformed or powerless individuals in medical experimentation has been going on for centuries. That still doesn’t make it right, but I have to say I have been more than a little fascinated as I learned just what we humans have done to others “for the greater good of the collective” throughout our history.

A Progressive Champion steps forward

When Smallpox was the scourge of the earth long before vaccination was developed, the practice of variolation was the accepted prophylaxis against Smallpox in much of Asia. Smallpox scaring and complications were common throughout Europe and the mortality rate was significant as well. Lady Mary Worley Mantagu is often credited for introducing variolation to Britain. Her husband was posted as Ambassador to the Ottoman Empire (Turkey today) and while stationed in Constantinople against her husband’s wishes she had their son variolated. Lady Mary was apparently severely scarred from Smallpox herself and in fact had no eyelashes as a result of her own illness and was determined her children would not suffer as she had. She also was instrumental in persuading many of her friends and family to undergo variolation for their children.

A Process is Born

King George and Princess of Wales Caroline, the reigning monarchs of England were intrigued about the success of the procedure and of course wanted the Royal Princesses protected. But first they had the Royal Surgeon make certain it was in fact safe for the young princesses. To insure the safety of the Royal Princesses the Royal Surgeon first had six condemned and jailed prisoners (male and female) variolated. He promised them amnesty if they survived. None of them died. This was good but not quite good enough for the Royal Highnesses. That was apparently a “Phase I” trial. Today clinical trials are often accompanied by catchy marketing generated names that resonate with the Pharmaceutical company or sponsoring entity and a lot of time and expense goes into choosing that catchy name and clever acronym. I think the most apt name for this next Phase II trial could have been “send in the orphans”.

Ten orphans from the St. James Orphans Asylum were selected and variolated. When they all lived The Princess Caroline decided the procedure was safe enough for the young Princesses. Still Variolation was not without problems, some studies show the death rate from the procedure to be as high as 5%, less than that of smallpox (15 – 20%) but not exactly odds that assured people.

The good doctor did what?

The celebrated Jenner vaccine protocol would have had certainly raised eyebrows today. Edward Jenner was a country doctor, but he was educated in London’s St. Georges Hospital under the famous surgeon of the day, Dr. John Hunter. Jenner was a keen observer of nature and was convinced of the prevailing theory of the time that people who recovered from the very benign illness of Cowpox never got Smallpox. When a local milkmaid named Sarah Nelmes came to see him with an obvious case of Cowpox sores on her hands Jenner saw his chance. Somehow he managed to convince a local farmer named Phipps to let him inoculate his son with Cowpox assuring him the boy would never suffer from Smallpox. Somewhat surprisingly the farmer agreed so Jenner inoculated young James who was six years old by making two cuts in his arm and pouring a vial of the Cowpox puss into the cuts. Young James came down with a mild case of Cowpox and quickly and quite nicely recovered.

Then came Jenner’s “Phase II” and if we were to name this study today it would be called “WTF RU NUTZ?”. Six weeks after pouring the cowpox into the kid’s cuts Jenner took puss from a dying Smallpox victim and again made an incision in young James arm and poured in the Smallpox puss this time. Whoa! Did the farmer sign up for this part of the experiment? Fortunately Jenner’s theory was right and young James did not come down with Smallpox. Had young James contracted Smallpox and died, Jenner would surely have faced a murder trial. If an IRB were to be presented with this proposal today their eyes would pop out of their head! The cynic in me actually can’t help but wonder if Jenner didn’t “have the goods” on the good farmer Phipps because I cannot imagine a father even considering such an action.

Meanwhile - back at the orphanage

Even after Jenner’s vaccine to prevent Smallpox was discovered we didn’t end the use of orphans as medical tools. The vaccine was effective, but how did it get manufactured? It was discovered that “arm to arm” inoculation was very effective. That meant once a person had the Cowpox virus inoculated into their body, it could then be extracted and inoculated into another person. Convenient since the only container for a human vaccine at that time was the human body. No such thing as a vial, ampoule or a syringe. Why orphans? It seems unbelievable today but orphans were considered to be the perfect solution. Society had fed and housed them, no one championed their cause. They were less troublesome than convicts (the other disposible group of the day).Usually you just had to have a nun watch over the orphans as opposed to guards, weapons and restraints for convicts.It really simplified that whole “chain of custody” process. Orphans, the perfect biological drug containers!

Not just an English practice

Next came the Balmis- Savony Expedition sponsored by another Royal House. King Charles IV of Spain had lost a son to Smallpox and announced that all the Spanish Colonies of America and Asia would in fact begin a vaccination program using the Jenner vaccine to wipe out Smallpox. The Balmis – Savony expedition was underway with orders to all civil and religious authorities to do what was necessary to insure vaccination of all the King’s subjects. Once again “queue the orphans”. A Royal edict was issued by Charles IV to take 20 children between ages 8 and 10 from La Coruna's Orphans' Home that had never had Smallpox. A plan was devised to pass the vaccine live, transmitting it from child to child as the skin lesions began to extrude lymph from Days 4 to 10 post-vaccination. The initial vaccination was performed in Madrid using 5 orphans who were sequentially inoculated on the way to La Coruna.

The ship was loaded with 21 orphans (along with one unlucky Nun) and the orphans were inoculated sequentially throughout the voyage to keep the vaccine alive until they reached their first stop – Puerto Rico and then apparently the orphans were systematically replaced with local orphans as the voyage worked its way through the Spanish colonies throughout the Caribbean and South American. Balmis picked up 25 fresh orphans in Mexico to transport the vaccine across the Pacific and ultimately on to Asia.

Fortunately we have less intrusive methods of transporting vaccines today. Syringes and vials immediately come to mind. Still, given our nature to take shortcuts and save costs as well as our tendency to use the subjects of convenience, I think history (ancient and recent) has provided us with a lot of good reasons for enhanced FDA oversight as well as a strong IRB process.

Regulations and regulators, considering our history, I am very much in favor of them!