Although the phase 1 to 3 approach remains the gold standard in clinical research, new designs and approaches are increasingly being used. In the Patient Advocacy Session 1 at the congress of EHA in Madrid, Dr Elihu Estey discussed some of the drawbacks of the current clinical trial designs, and compared the on- and off-protocol treatments in patients with a hematological malignancy. In addition, Dr Bernhard Wörmann discussed the current and upcoming versions of the EU Clinical Trials Directive.
Physicians can treat patients ‘off-protocol’ if they believe that this treatment is in the patient’s best interest. “To gain insight in the off-protocol treatment of cancer patients we evaluated 208 patients with acute myeloid leukemia (AML) who were treated on-protocol and 189 AML patients treated off-protocol. Reasons for off-protocol treatment included medical reasons like a poor performance status, insufficient cardiac function or an urgency to be treated off-protocol. In addition, there could be ‘logistical’ reasons such as the patient’s or physician’s preference, or financial reasons. In some cases the reason was unknown. When we determined the relapse-free and overall survival of newly diagnosed patients, the patients treated off-protocol because of medical reasons did worse than patients treated on-protocol or those off-protocol due to logistical reasons. This difference was less clear for patients with relapsed and/or refractory AML. After accounting for known reasons, off-protocol treatment was still associated with poorer outcome, suggesting that physicians adept at recognizing patients who will do poorly. Questions that emerge following these results are, for instance, ‘How does such selection bias affect conclusions from published trials?’ and ‘Is exclusion of patients for medical reasons discrimination?’”, said Dr Elihu Estey (Seattle Cancer Care Alliance, Seattle, USA).
In the second part of his presentation Estey discussed some of the drawbacks of the current clinical trial designs and briefly touched upon alternative designs. Estey: “The phase 1 to 3 approach ignores clinical reality because it focusses on only one outcome while patients are interested in several. Furthermore, it generally ignores the heterogeneity of the disease examined, delays comparison in a randomized trial and is insufficiently adaptive. Finally, phase 1 to 3 trials take too long to complete because the targeted improvement is too low.”
The primary goals of the EU Clinical Trials Directive issued in 2001 were to standardize the regulation and quality of clinical trials, ensure patient safety, and harmonize and simplify administrative procedures. “However, in fact it rather increased the administrative burden and costs of staff and insurances. As a result, the number of clinical trials decreased dramatically in most EU-countries. These results led to a new initiative initiated in 2014. One of the key changes in this initiative is the incorporation of a new electronic portal for submission, assessment and communication. Furthermore, the new directive is characterized by a uniform approval procedure, a rigid time schedule with short deadlines, only one approval document and specific requirements for minimal intervention studies. The new regulation is anticipated to become applicable in October 2018”, said Dr Bernhard Wörmann (German Society of Hematology and Oncology, Berlin, Germany).
Approval of new agents does not automatically lead to market access. Furthermore, market access varies greatly between countries, including those of the EU. Wörmann: “For instance, while in the USA and UK most drugs do access the market upon approval, most approved drugs do not enter the markets of, for instance, Turkey and India. This is mainly due to the incorporation of a risk benefit assessment, which varies among countries. For instance, in Germany this assessment is generally fast but often concludes that about 60% of the newly approved drugs has no additional benefit, resulting in denial of market access. This is predominantly caused by a discrepancy between the approval criteria used by the EMA versus those applied by the EU-member states.”