Advocating for a Return to Common Sense in Clinical Research

In his June 2017 Editor’s  Corner (“Contract Research Agonizations”), ASH Clinical News’ Editor-in-Chief Mikkael Sekeres, MD, MS, called for an end to the bureaucratic madness that contract research organizations (CROs) have introduced to the clinical trials process. The article inspired an impassioned response from our readers, with several writing in to express solidarity and share their own experiences with site initiation visits.

The responses came from far and wide: Steven Le Gouill, MD, PhD, from the Department of Hematology at Nantes University Hospital and the Centre Hospitalier Universitaire in France, wrote that he “hoped [the] article will be a first step in bringing back some bon sens in clinical research.”

Below, Pr. Le Gouill, Simon Rule, MD (Plymouth University, United Kingdom), and more than 80 European colleagues present a call for a return to common sense in clinical research.

The editorial by Mikkael Sekeres, MD, MS, in the June issue of ASH Clinical News perfectly describes a site initiation visit (SIV) conducted by what Dr. Sekeres termed a “contract research agonization” (CRA) and the madness that modern clinical research has become. The constant reference to “quality” has paradoxically became synonymous with mindless, needless, and ultimately counterproductive bureaucracy. It is time to start questioning the necessity of some aspects of the clinical trials data-collection process, particularly those that cause daily hassles before, during, and after a clinical trial – sometimes years after publication.

Like our American colleagues, European investigators are plagued by the CRA parasite. At this stage, it is worth repeating the definition of a parasite: a living being feeding itself at the expense of the organism that shelters it. The SIV described by Dr. Sekeres is sadly identical to the SIV in Europe, with the addition of some local complications. For instance, we must date all documents according to U.S. format (MM/DD/YYYY) rather than European format (DD/MM/YYYY). If this is not followed, the documents have to be changed and multiple queries ensue.

European investigators also complain of the countless emails that flood their inboxes documenting serious adverse events (SAEs) and suspected unexpected serious adverse reactions (SUSARs). This is all done in the name of safety, but here is where the paradox lies. The deluge of SAE reports identifies toxicities (such as neutropenic sepsis on the chemotherapy control arm, or infusion-related toxicity with a 20-year-old antibody therapy, or progressive disease in tumors unrelated to the trial in question). Add to that the SUSAR reports that are evidently not serious, nor even expected, and toxicity-reporting becomes less safe because no one can see the wood for the trees.

No one in the industry takes responsibility for looking for true toxicities of concern, so researchers are sent everything. The CRA industry has created its own rules requiring electronic sign-off to acknowledge receipt of these reports. No one has the time to read these, and, if one does, there is rarely (if ever) any toxicity information that is valuable to the clinician running the trial. Trials are now less safe as a consequence.

There are also the never-ending passwords to constantly renew and the famous questionnaire of feasibility emailed to you that invariably begins with the same question: “What is your email address?”

We are reaching a point where the paperwork and what we are being asked to do is descending into absurdity. Are increased administrative procedures the price we must pay for a guarantee of the quality of scientific projects? Are we all condemned to say nothing, do nothing, and suffer? The answer to all these questions must be “non, no, nein, and niet!”

We, the doctors and researchers who treat patients, are the true clinical research specialists. It is therefore our duty to stop the administrative inflation introduced in the name of “good practice” that is beginning to kill clinical research, demotivate clinical research teams, scare away young clinicians, and unnecessarily disperse the limited financial resources that should go toward improving care and science. How could we not denounce a business model that does nothing for patients, unreasonably increases the cost of clinical trials, and ultimately benefits only the industry that invented it?

Worse, these harassments inhibit all creativity and initiative. Imagine what would have happened if CRAs had preceded the discovery of fire some 400,000 years ago. Humanity would have remained in the dark, living in caves, eating raw meat, and hoping not to be eaten. And why? Because humanity would not have been able to prospectively investigate the interest of fire according to the so-called good practices, as established by CRAs. If humanity had been able to prospectively investigate the role of fire according to modern research criteria, the conclusion of the phase I trial would have been that fire is too toxic because of too many AEs and SAEs, such as grade 3 “meat overcooking,” grade 4 “burns,” and grade 5 “cave fire.”

Today, the question of interest is no longer whether clinical research should continue on its path of administrative absurdity, but how to stop this madness without harming the quality of scientific data. The pharmaceutical industry needs to engage properly with the regulators and stop interpreting what they believe is expected of them. Those of us who still run academic studies within the same regulatory frameworks know full well that most of what is being asked for in the name of quality and safety is not required.

The CRAs have created a lucrative industry for themselves and needlessly generate work that only serves to perpetuate their existence with no tangible benefit to the patient. In the medical world, we are mandated to produce evidence before we can change practice; we would like to see any evidence that clinical research is safer today than it was 10 years ago.

We believe that the time has come for academic societies (such as the American Society of Hematology, the American Society of Clinical Oncology, the European Society for Medical Oncology, and the European Hematology Association) and cooperative groups involved in clinical research to challenge this pernicious culture and produce recommendations for good practice. This needs to be done in concert with the regulators, but the interpretation of safety and quality should not rest with those at arm’s length from the patient or the drug company, and whose business depends on generating paperwork to justify spiralling costs.
It is our duty as both clinicians and citizens to reverse this trend and bring common sense back to research. Ultimately, it is the patient who will miss out on innovation if this continues.

Signed by:

Pr S. Le Gouill (Nantes Medical University, Nantes, France) and Pr S. Rule (Plymouth University, Pymouth, UK) and (in alphabetic order):

Pr L. Ades, Hôpital Saint Louis, Paris, France;

Pr M. Attal, Institut Universitaire du Cancer Toulouse, Toulouse, France;

Dr Y. Beguin, Université de Liège, Liege, Belgium;

Dr C. Bonnet, Université de Liège, Liege, Belgium;

Pr D. Bordessoule, Limoges Medical University, Limoges, France;

Dr P. Brown, Rigshospitalet Copenhagen, Denmark;

Pr C. Buske, University Hospital Ulm, Germany;

Pr G. Cartron, Montpellier University Hospital, Montpellier, France;

Dr O. Casasnovas, Dijon University Hospital, Dijon, France;

Pr B. Coiffier, Hospices civils de Lyon, Lyon, France;

Pr G. Collins, Oxford Cancer and Haematology Centre, UK;

Pr F. D’Amore, Aarhus Universitet hospital, Aarhus, Denmark;

Pr A. Davies, Southampton University Hospital, UK;

Dr R. Delarue, Hopital-Necker, AP-HP, Paris, France;

Pr A. Delmer, Reims Medical University, Reims, France (President of the French Society of Hematology);

Pr T. Dimopoulos, Natinal and Kapodistrian University of Athens, Greece;

Dr J. Doorduijn, Erasmus MC Cancer Institute, Rotterdam, Netherlands;

Pr C. Doyen, CHU UCL NAMUR (Godinne), université catholique de Louvain, Belgium;

Pr M. Dreyling, Klinikum der Universität München, Germany;

Pr A. Engert, University Hospital of Cologne;

Pr P. Fenaux, Hôpital Saint Louis, Paris, France;

Pr P. Feugier, Nancy Medical University, Nancy, France;

Dr G. Follows, Cambridge University Hospitals, UK;

Dr A. Fosså, Oslo University Hosptial, Norway;

Dr C. Fox, Nottingham University Hospitals, UK;

Pr P. Ghia, Università Vita-Salute San Raffaele, Milano, Italy;

Pr. M. Ghielmini, University of Lugano, Switzerland;

Pr C. Gisselbrecht, Hôpital Saint Louis, Paris, France;

Dr M. Gomez Da Silva, Insituto Portugues de Oncologia, Lisbon, Portugal;

Pr E. Gyan, Tours Medical University, Tours, France;

Pr C. Haioun, AP-HP Henri-Mondor, Creteil, France;

Pr M. Hallek, University Hospital of Cologne, Germany;

Pr O. Hermine, Hopital-Necker, AP-HP, Paris, France;

Pr G. Hess, University of Mainz, Germany;

Pr W. Hiddemann, Klinikum der Universität München, Germany;

Pr P. Hillmen, Leeds University Hospital, UK;

Dr C. Hulin, Bordeaux Medical University, Bordeaux, France;

Pr M. Hunault, Angers Medical University, Angers, France;

Pr G. Jackson, Newcastle University Hospital, UK;

Dr M. Jerkeman, Lund University, Sweden;

Pr P. Johnson, Southampton University Hospital, UK;

Pr. W. Jurczak, Jagiellonian University, Kraków, Poland;

Pr E. Kimby, Karolinska University Hospital Stockholm, Sweden;

Dr M. Ladetto, Ospedaliera Santi Antonio, Alessandria, Italy;

Pr T. Lamy, Rennes Medical University, Rennes, France;

Pr V. Leblond, La pitié Salpétrière AP-HP, Paris, France;

Pr X. LeLeu, Poitiers Medical University, Poitiers, France;

Dr PJ Lugtenburg, Erasmus MC Cancer Institute, Rotterdam, Netherlands;

Dr M. Macro, Caen Medical University, Caen, France;

Pr A. Marc, Université de Louvain, Louvain, Belgium;

Pr G. Marit, Bordeaux Medical University, Bordeaux, France;

Pr M. Martelli, Sapienza University of Rome, Italy;

Dr A. McMillan, Nottingham University Hospital, UK;

Pr N. Milpied, Bordeaux Medical University, Bordeaux, France;

Pr M. Mohty, Hopital Saint-Antoine, Paris, France;

Pr P. Moreau, Nantes Medical University, Nantes, France;

Pr F. Morschhauser, Lille Medical University, Lille, France;

Dr B. Østenstad, Oslo University Hosptial, Norway;

Pr C. Ottensmeier, Southampton University Hospital, UK;

Dr A. Perrot, Nancy Medical University, Nancy, France;

Pr A. Pettitt, Liverpool University Hospital, UK (Chair of the NCRI Haematological Oncology CSG);

Pr. M. Pfreundschuh, Universität des Saarlandes Homburg, Germany;

Pr C. Recher, Institut Universitaire du Cancer Toulouse, Toulouse, France;

Dr V. Ribrag, Institut Gustave Roussy, Villejuif, France;

Pr M. Rummel, Universitätsklinik Giessen, Germany;

Pr P. Rutkowski, Maria Sklodowska-Curie Institute – Oncology Center, Warsaw, Poland;

Pr G. Salles, Hospices civils de Lyon, Lyon, France;

Pr N. Schmitz, Asklepios Hospital St Georg, Hamburg, Germany;

Pr K. Smedby, Karolinska University Hospital Stockholm, Sweden;

Pr. P. Sonneveld, Erasmus MC Cancer Institute, Rotterdam, Netherlands;

Dr K. Stamatopoulos, Center for Research and Technology Hellas, Thessaloniki, Greece;

Dr N. Stavroyianni, G. Papanikolaou Hospital, Thessaloniki, Greece;

Pr H. Tilly, Centre Henry Becquerel, Rouen, France;

Pr M. Trneny, Medicine University Praga, Czek Republic;

Pr E. Van Den Este, Université catholique de Louvain, Belgium;

Pr N. Vey, Centre Paoli Calmette, Marseille, France;

Dr C. Visco, Ospedale San Bortolo, Vicenza, Italy;

Pr U. Vitolo, Città della Salute e della Scienza di Torino, Torino, Italy;

Pr J. Walewski, Maria Sklodowska-Curie Institute – Oncology Center, Warsaw, Poland;

Pr I. Yakoub-Agha, Lille university hospital, Lille, France;

Pr PL Zinzani, Bologna University, Italy.