Kim,

To me the 3 cases are not clear, all cancer trials are with therapeutic intent. Were these trials with a new investigation drug? What type of cancer these patients had: advanced refractory metastatic cancer? If the response is yes to both the questions then means to make them eligible are justified..I wonder how an incomplete paper was accepted and published in NEJM.

Excellent article and very complicated topic.

Most clinical research always involves an irremediable conflict of interest. The fact that a patient is subjected to blinded "therapy" with potentially harmful agents with unproven and only potentially therapeutic benefits condemns most trials to a breach of the fundamental tenet of doctor-patient relationship. Simply put, if the "therapy" will not, to a reasonable degree of certainty, benefit the patient then it fall outside of the doctor's fiduciary duty to the patient. In fact there may be many beneficiaries of the patient's participation- the doctor, society, pharmaceutical companies, or stockholders. The patient/subject is not a reliable beneficiary of medical care. A reasonable degree certainty as to therapeutic superiority further breaches the physician's fiduciary duty since, axiomatically, one of the agents has a reasonable degree of inferiority. Thus, a physician is knowingly using an inferior agent or technique.

The fallacious belief that many patients have has a name- "therapeutic misconception." Therapeutic misconception arose, as a term, approximately 25 years ago to describe the false belief held by study participants that participation in a study would actually benefit the individual patient. That is not the purpose of most studies.

In the particular cases, cited by the Toronto researchers, they report a form of research misconduct. The researchers "manipulated" patient data to allow entry into studies by unqualified patients. This act differs only quantitatively, not qualitatively, from simply fabricating the same entry data. Further, it may make the entire body of results uninterpretable thus breaching the researchers wider professional duty to colleagues.

Why, you might ask, would someone do such a thing? There are several reasons.
1) In the most generous light, it would be to allow someone to have access to a drug otherwise unavailable. While this might seem noble, it's also a random experiment- recall that these are therapeutic trials of potentially unproven agents. In such a case if the patient/subject is entered into the study and receives the control drug then there may be no possibility of therapeutic effect.
2) In many trials in the US the researcher is paid based on enrollment of subjects. Therefore each additional subject brings in more money.
3) The misuse of these techniques may be based on some non-therapeutic relationship between doctor and patient.

In the US such research misconduct would almost certainly be fraud. As intrinsically unfair as clinical research is to patients, this practice if frankly abusive. The bottom line is that unless these techniques are expressly permitted then they are fundamental failures of medical professionalism.

As stated in my first comment, it may be ethical and logical for a advanced melanoma patient with BRAF gene mutation to be primed with blood transfusions to meet Phase I protocol eligibility criteria. Why exclude eligible patients from new Phase I drugs with high 80% response.rates. Changing a few lab parameters by blood transfusions or other means should be acceptable?

One of the other issues to consider is skewing the data and potentially preventing a drug that works from being approved. If people with low Hemoglobins are excluded, and somebody receives a blood transfusion to get around the exclusion criteria, then it is likely that upon review of follow-up data, it will look like their subsequent hemoglobin levels have fallen (whereas it may have simply been the baseline). This may lead investigators (and the FDA) to mistakenly believe that the drug causes anemia when it doesn't, which would stop the progress of the drug based on bad data before it started.

Exclusion criteria are also generally created to exclude those who have a high mortality. The reason is because it is hard to show that a drug is beneficial (or harmful!) if the patients involved in the trial are going to die whether they receive treatment or not.

Giving people a blood transfusion to get around exclusion criteria is unethical. It may seem like one is providing some hope to the most severe of patients; but in reality, one may just be halting drug development for those who could truly benefit.