The Chimeric Investigator, an Endangered Species

Huib M Vriesendorp, MD, PhD & Hal A Droogleever Fortuyn, MD, PhD

What is a chimeric investigator?

During his long and remarkable career Professor Dick van Bekkum (1925-2015) was a PhD thesis adviser to 50 different investigators, working in the Radiobiology Institute, TNO, Rijswijk, The Netherlands. After the investigators had become MD/PhD’s, Dick told them they acquired a new title: ‘Chimeric Investigator’(CI). A CI has two ‘genotypes’, like the ‘Radiation Chimera’ (RC) after conditioning with Total Body Irradiation and a successful allogeneic Bone Marrow Transplant. RC maintain their original, ‘own’ genotype but carry the genotype of the Bone Marrow donor in their hemopoietic tissues. A Chimeric Investigator has both an MD ‘genotype’ and an Investigator ‘genotype’: a good starting point for translating serious problems of patients into an ‘experimental’ question. Or like Dick van Bekkum used to say to his PhD students: ‘What do you want to know?’

A well trained CI can formulate a ‘null’ hypothesis, i.e. an experimental plan for improving the problem encountered in one or more of his/her patients. If the null hypothesis is correct the Quality of Life of several study patients will improve. When in a 20 patients such results are not obtained with significant p-values based on Poisson statistics, the null hypothesis can be rejected or in Karl Popper and Peter Medawar’s term be ‘falsified’. (1,2)

If the ‘null-hypothesis’ cannot be falsified and more than 1 out of 4 patients appears to benefit from the treatment, further studies are needed to to make the treatment available and effective for more patients. Popper posits null-hypotheses can never be proven to be correct, only ‘compatible’ with the available new test results.   The advantage of this approach:

Marginal, toxic, new therapies can be discarded; Effective therapies can be selected for further improvement in cheap (less than $200.000,) quick  (shorter than 2 years) studies. Popper also suggests studies without a testable ‘null’ hypothesis that can be falsified should not be done.

Where have all the Chimeric Investigators gone?

Most MD, PhD’s are no longer doing their own clinical research studies, but participating in more financial rewarding double blind randomized, phase 3 studies. Such studies do not have a falsifiable null-hypothesis. The question being asked is: ‘Is study arm A better than study Arm B? An answer with a p-value of <0.05 will be obtained for one or the other arm. This will take a long time, cost a lot of money and not provide better Quality of Life for many patients, because both arms have to be ‘equipoise’, similar risks for benefits and side effects.

Professor David Sackett, who introduced the term ‘evidence based medicine’ for the first time, is concerned as well. In 1996 he publishes in the British Medical Journal:

‘Evidence based medicine is not ‘cookbook medicine’. Some questions about therapy do not require randomized trials (successful interventions for otherwise fatal conditions). We must follow the trail to the next best external evidence and work from there.’

Physician investigators are receiving money for each patient entered on a ‘Big Pharma’ study. In the Netherlands members of the Institutional Review Board, the Dutch acronym being Medical Ethical Testing Committee, are being paid for their services in the METC by Big Pharma. In the USA Big Pharma pays high fees to the FDA, whose employees eventually leave the government for higher salaries in the Pharmaceutical industry.

Big Pharma has also started Direct to Patients (DTP) advertising on billboards, TV commercials, Printed Media. ‘Ask your doctor whether you are a candidate for medication X?’ This has led to the laughable advice to patients/ candidates for a drug for male impotence and prostate hypertrophy to call their doctor for an erection lasting more than 4 hours. Or patients/candidates for a monoclonal antibody for ulcerative colitis are told to warn their doctor if they have met people with tuberculosis. Or MDAnderson Cancer Center paying for commercials during the Olympic Games in Rio or advertising in the NewYorker and the Smithsonian telling viewers/readers they are going to ‘make Cancer History’, suggesting MDAnderson Cancer Center is the only or at least the best institution to make cancer history without providing any scientific evidence to support their slogan.

The autonomy of the doctor-patient relationship

New therapeutic procedures can be investigated in an ethical manner in human patients, if both doctor and patient are ‘autonomous’, that is are able to understand and consent to or reject the proposed study. Doctors/CIs should not have a conflict of interest. Both doctor and patient sign the study consent form. The consent form contains three elements, defined as the ‘Belmont Principles’: Respect, Beneficence and Justice. The consent form lets the doctor and/or the patient terminate the study, if the quality of life of the patient decreases significantly, without changing the doctor-patient relationship.

The studies accrue one patient at a time, till Poison statistics indicate that less than 1 in 4 patients benefits from the treatment (stop study) or that 1 in 4 patients benefits from the new therapy. (Enroll more patients)

This P2T approach: 1. Renews the interest of doctors in doing their own studies again, 2.  Decreases investments in new therapies, which at best generate minimal improvements, 3. Eliminates the need for phase 3 studies, double blind randomized trials. Which well educated physician wants to study patients, without knowing which treatment his/her patient is on?

Many specialists traditionally involved in the approval of clinical research studies, such as ethicists, government regulators, pharmaceutical industry, statisticians, religious leaders, lay persons, most of them members of IRB/METC will protest against this more empiric manner of doing research as dangerous and unscientific. We argue that most IRB members have never treated a patients and are not autonomous, i.e. have conflicts of interest and have never read or understood ‘The Logic of Discovery’.

  1. Karl Popper, The Logic of Discovery, 1959, ISBN 0-415-27844
  2. Peter Medawar, The Strange Case of the spotted mice and other classic essays on science. Oxford University Press, 1961
Karl Popper

True ignorance is not the absence of knowledge but the refusal to acquire it.

Dick van Bekkum

What do you want to know?