The Double Edged Sword

Or you may want to use the metaphor of the apple of the tree of knowledge.  Whatever metaphor you use, knowledge can be wonderful, liberating, life saving and search for knowledge is the best part of the human spirit. Search for knowledge can also be devastating, destructive, and in the wrong hands it can be downright criminal.

Clinical Trials and the Search for Answers

I am a big fan of clinical trials – well thought out, well conducted and ethical clinical trials. Without clinical trials and their hard won knowledge, we will never be able to change the word “incurable” in front of CLL.

Sometimes our members get all excited about some breathless “miracle of the month” story in the lay-press, talking about how “leukemia” (which one? There are dozens of different leukemias, each of them distinct and needing different therapy approaches) is now cured - in the lab test tube. Typically, this is how the story goes: some CLL cells in a glass dish are treated with the new miracle drug candidate and the cells died. Heck, I can do that with mouthwash!  The alcohol in it would kill most cells, including CLL cells. But no one would seriously consider mouthwash is a cure for CLL. The amount of time it takes to go from the “Aha!!” moment in a lab test to a clinically viable therapy option that patients can use to live longer and healthier lives can be 10 years or more  - if everything goes exactly right.

How many “Aha!!” moments make it all the way? Less than a fraction of 1%. Somewhere along the line, as the research goes from glassware experiments through mice and other animals and finally to human clinical trials, the “miracle” generally loses its shine. Adverse effects start showing up, sometimes they are so many or so dangerous that research with the concept drug comes to a grinding halt. Sometimes, the drug that killed CLL cells in such large numbers in the lab does very little when injected into the human body. Sometimes money runs out before the drug can be completely tested and its sponsors walk away. And sometimes, more often than you would think, the human studies go no where fast because recruitment of volunteers becomes a huge hurdle. Time is money. The longer it takes to recruit patients, the more the study will cost.

Not all Clinical Trials are Created Equal

Everyone talks about the need for clinical trials, how we need them. There are a couple of vocal patients out there that want better patient participation in clinical trials, all clinical trials. That is almost a motherhood and apple-pie statement. But I strongly believe a few well chosen caveats are in order. We need well-researched, well-designed clinical trials. We need clinical trials that are run to increase understanding of this disease and thereby find potential therapies (dare I say CURE?) for CLL. We need clinical trials whose designs take patient safety and quality of life into account. And above all, we need clinical trials that pay attention to the concept of “informed consent” – the spirit of it and not just legal wording to protect the researcher and his institution from lawsuits.

It saddens me that so many clinical trials are done with an eye on corporate profits rather than patient welfare. Consider trial design where patients are randomized into two groups, one group gets the experimental drug, the other group (the “control group”) gets conventional therapy. If the group that got the experimental drug does better than the control group, the new drug is welcomed as an addition to our available therapy choices. This is the “gold standard” of clinical trial design, two well matched groups of patients randomized into the experimental and control groups in order to eliminate researcher bias, one-on-one comparison where we hope to get clear answers.  And if the groups are sufficiently large, the answers we get will be statistically significant.

Aha. But the devil is in the details my friends. Very few large scale and double arm, randomized studies are done anymore, they cost too much money. Most often, research institutions do single arm studies where everyone gets the experimental drug and the results are then compared against historical norms. Sounds good, right?

Only problem is human bias and human nature. Ever heard of cherry-picking? CLL lends itself particularly well to flawed results on account of researchers gilding the lily. If you pick subtly biased group of patients for your single arm study, patients with just slightly better than average prognostic indicators, slightly better overall health, just a tad younger, just a tad less entrenched disease than “historical norms”, who can tell the difference? In an apples to carrots comparison, how can we tell the difference between different therapy options? Several of you asked about FCR statistics, why they are so different in the various studies we reported in our recent articles. Fortunately, there have been enough studies (some of them well conducted double arm studies) that we can feel comfortable about the overall perspective of FCR therapy – even if we don’t quite buy the hyped up statistics in some of the trials. Even with all the caveats, all the warts that we wish were not there, we are lucky to have had this research done.  FCR is a very powerful drug combination and there is emerging consensus that CLL patients will live longer in future because of it.

Many things contribute to faulty results and fake conclusions: researcher bias; cherry-picking of trial participants. small scale studies that are almost anecdotal and without statistical significance; subset analysis (where the researchers look at smaller subsets of people in their study, looking until they find the result that ‘proves’ their theory); out and out fraud where companies / researchers deep-six results they do not like or want and publicize selected results that help their profits or careers.

Apples to Carrots Comparisons

A recent clinical trial of Treanda (bendamustine) has been discussed on this site and elsewhere. This was a two arm trial. The results of this trial were pivotal in getting Treanda FDA approval as a CLL drug. Here is my problem with this trial in a nutshell. One group of patients got Treanda. The control group got less than optimum therapy with chlorambucil. Tada! To no one’s surprise, this straw-man comparison showed Treanda worked better than a sub-par regimen of chlorambucil. Don’t get me wrong. Treanda is another drug that works in CLL and I am glad to have more options available to our patients. But this particular trial obeyed the letter of the law and flouted the spirit of it to a large degree.

How would you like to have been one of the volunteers for this trial, randomized to the straw-man control group? What did it cost the patients in terms of time, window of opportunity and unnecessary toxicity without sufficient benefit to be in this control group? Would you say they were suckered in order to make Treanda look good? I am just asking. And I am not the only one. Several well known and respected CLL experts felt uncomfortable about this trial. One or two of them would even acknowledge it in public. It is hard to get these guys to go on the record. Who wants to rock the boat?

The Bigger Picture

Each and every time an individual patient considers participation in a clinical trial, there is a chance for altruism, optimism, greatness – or unfair tactics. Patient consent forms are written by researchers, but overseen by lawyers whose only aim is to protect the researcher and institution from getting sued – that is the sad truth of it. Internal ethics and oversight committees are staffed by research and industry folks – none of whom are particularly interested in totaling their careers by rocking the boat. The few “patient advocates” on these boards often have no science background, totally blown away by the jargon and intimidated into being little more than rubber stamps. True, there are some stellar exceptions to this and I salute them.

But by and large, there are valid reasons why patients are not volunteering in droves to participate in clinical trials. The system is broken; it does not play fair; there are too many vested interests; too much money controlling the results to the detriment of good science; last but by no means least, it does not really respect patients and their rights. I really mean that word, RESPECT. Few clinical trial designs truly consider the individual patient being recruited, that he is not just a number in a data base, he is an individuals with a life to live, family that loves him and depends on him.  A while ago a large drug company asked my help in understanding why their clinical trial had so much trouble recruiting patients.  Besides the obvious toxicity of their very immune suppressive drug combination, the company failed to see that patients are not lab rats, they would not want to be subjected to a bone marrow biopsy after each cycle of therapy.  The researchers thought the data would be nice to have - the patients rightly thought otherwise.

The Bad Old Days

So, what caused me to have this particular brain melt-down on the whole business of medical research, why we need it so desperately and what can go terribly wrong with it? Below is a link to a news story that you should read in full, I have a few quotes from it for your convenience. The incidents it reports happened in the lifetime of most of our patients. It happened after the World War II and the well documented atrocities of the Nazi medical experiments on helpless victims in concentration camps. This story is not about war, not about concentration camps. It is about doctors that truly forgot their oath to do no harm. It is about one group of people treating another group of people as less than human, as so much garbage to be abused in any fashion they chose. And who was the perpetrator of this inhuman medical atrocity? The American medical establishment.

Those were the bad old days. I am pretty sure such horrific experiments are not conducted anymore, and I most sincerely hope my tax dollars do not pay for such things. Now we need to worry about more subtle nuances. When is informed consent truly informed? When does it become a crime to recruit patients without disclosing all the facts and conflicts of interest, or gloss them over with a wink and a nod? Or buried under deliberately confusing jargon?  When does the profit motive totally overwhelm good science? When are our voices heard, when do our advocates get a seat at the table where decisions are made? When do we get the respect we deserve, as we put our lives on the line and participate in clinical trials?

It is a hard road to travel.  But travel it we must, with our eyes wide open.  Do it for the fat lady.


U.S. Apologizes for Syphilis Experiment in Guatemala


October 1, 2010, New York Times.

From 1946 to 1948, American public health doctors deliberately infected nearly 700 Guatemalans — prison inmates, mental patients and soldiers — with venereal diseases in what was meant as an effort to test the effectiveness of penicillin. American tax dollars, through the National Institutes of Health, even paid for syphilis-infected prostitutes to sleep with prisoners, since Guatemalan prisons allowed such visits. When the prostitutes did not succeed in infecting the men, some prisoners had the bacteria poured onto scrapes made on their penises, faces or arms, and in some cases it was injected by spinal puncture.

If the subjects contracted the disease, they were given antibiotics. “However, whether everyone was then cured is not clear,” said Susan M. Reverby, the professor at Wellesley College who brought the experiments to light in a research paper that prompted American health officials to investigate.

The revelations were made public on Friday, when Secretary of State Hillary Rodham Clinton and Health and Human Services Secretary Kathleen Sebelius apologized to the government of Guatemala and the survivors and descendants of those infected. They called the experiments “clearly unethical.”

In a twist to the revelation, the public health doctor who led the experiment, John C. Cutler, would later have an important role in the Tuskegee study in which black American men with syphilis were deliberately left untreated for decades. Late in his own life, Dr. Cutler continued to defend the Tuskegee work. In 1972, it was revealed that, even when early antibiotics were invented, doctors hid that fact from the men in order to keep studying them. Dr. Cutler, who died in 2003, defended the Tuskegee experiment in a 1993 documentary.

The Nuremberg trials of Nazi doctors who experimented on concentration camp inmates and prisoners led to a code of ethics, though it had no force of law. In the 1964 Helsinki Declaration, the medical associations of many countries adopted a code. The Tuskegee scandal and the hearings into it conducted by Senator Edward M. Kennedy became the basis for the 1981 American laws governing research on human subjects. It was preceded by other domestic scandals. From 1963 to 1966, researchers at the Willowbrook State School on Staten Island infected retarded children with hepatitis to test gamma globulin against it. And in 1963, elderly patients at the Brooklyn Jewish Chronic Disease Hospital were injected with live cancer cells to see if they caused tumors.