Gisela Schott

The Financing of Drug Trials by Pharmaceutical Companies and Its Consequences: Part 1: A Qualitative, Systematic Review of the Literature on Possible Influences on the Findings, Protocols, and Quality of Drug Trials

BACKGROUND In recent years, a number of studies have shown that clinical drug trials financed by pharmaceutical companies yield favorable results for company products more often than independent trials do. Moreover, pharmaceutical companies have been found to influence drug trials in various ways. This paper provides an overview of the findings of current, systematic studies on this topic. METHODS Publications retrieved from a systematic Medline search on this topic from 1 November 2002 to 16 December 2009 were independently evaluated and selected by two of the authors. These publications were supplemented by further ones found in their references sections. RESULTS 57 publications were included for evaluation in Parts 1 and 2 of this article. Published drug trials that were financed by pharmaceutical companies, or whose authors declared a financial conflict of interest, were found to yield favorable results for the drug manufacturer more frequently than independently financed trials whose authors had no such conflicts. The results were also interpreted favorably more often than in independently financed trials. Furthermore, there was evidence that pharmaceutical companies influenced study protocols in a way that was favorable to themselves. The methodological quality of trials financed by pharmaceutical companies was not found to be any worse than that of trials financed in other ways. CONCLUSION Published drug trials that are financed by pharmaceutical companies may present a distorted picture. This cannot be explained by any difference in methodological quality between such trials and trials financed in other ways.

Immunophenotype and clinical characteristics of CD45-negative and CD45-positive childhood acute lymphoblastic leukemia

Abstract To evaluate the expression pattern of the leukocyte common antigen CD45 in acute leukemias and to investigate whether the lack of CD45 expression in childhood acute lymphoblastic leukemia (ALL) is associated with other immunophenotypic features and a distinct clinical behavior, we have carried out extensive immunophenotypic analyses of bone marrow and peripheral blood samples from 638 patients with childhood B-cell precursor (n=529) or T-lineage ALL (n=109). All 638 patients were enrolled in the German ALL-BFM 90 and ALL-BFM 95 trials. CD45 was detected on the surface of childhood ALL cells (cut-off ≥20% positive cells) in only 88.7% (n=566) of all cases. Among 529 patients with childhood B-cell precursor ALL, 12.9% (n=68) did not express CD45, compared with only 3.7% (n=4) of patients with childhood T-lineage ALL (p<0.001). In the B-cell precursor ALL subtypes, the highest frequency of CD45- cases (15.1%) was observed in common ALL (56/372) compared with only 7.2% in pro-B ALL (3/41) and 7.8% in pre-B ALL (9/116). Assessment of clinical parameters (age, organ enlargement, WBC, etc.) and event-free survival did not reveal significant differences between CD45- and CD45+ patients. Myeloid antigen coexpression was not correlated with CD45 expression. The mean percentage of antigen expression for CD34, CD10, TdT, CD22, and CD24 was significantly higher in children with CD45- B-cell precursor ALL than in those with CD45+ B-cell precursor ALL. In 28 patients with B-cell precursor ALL, cell cycle analyses of freshly isolated leukemic cells were performed with propidium iodide (PI) staining and flow-cytometric analysis. The percentage of cells in S-phase was inversely correlated to the percentage of CD45+ cells (r=-0.48, p<0.05). With two-parameter analysis of CD45-fluorescein isothiocyanate (FITC)- and PI-stained cells in nine patients with a percentage of CD45+ cells between 40 and 60%, two populations were distinguishable in a single patient. It was shown that the CD45- subpopulation had a higher percentage of cells in S-phase than the CD45+ subpopulation (10.7±4.0 vs. 2.7±1.8, p<0.007). We conclude that the lack of CD45 expression contributes to the identification of a distinct functional and immunological subgroup of B-cell precursor ALL, but that it has no significant impact on clinical behavior or on therapy outcome in childhood ALL.

The Financing of Drug Trials by Pharmaceutical Companies and Its Consequences: Part 2: A Qualitative, Systematic Review of the Literature on Possible Influences on Authorship, Access to Trial Data, and Trial Registration and Publication

BACKGROUND In recent years, a number of studies have shown that clinical drug trials financed by pharmaceutical companies yield favorable results for company products more often than independent trials do. Moreover, pharmaceutical companies have been found to influence drug trials in various ways. This overview of current, systematic studies on this topic is intended to identify and characterize the particular aspects of the performance of a drug trial that can be affected by financial support from a pharmaceutical company. METHODS Publications retrieved from a systematic Medline search on this topic from 1 November 2002 to 16 December 2009 were independently evaluated and selected by two of the authors. These publications were supplemented by further ones found in their references sections. RESULTS 57 publications were included for evaluation in Parts 1 and 2 of this article. A number of studies revealed that many trials financed by pharmaceutical companies-in some cases, as many as half of all such trials-are never published. Moreover, multiple publications of the same findings were found, and some reports were found to include selectively published data. Further studies revealed evidence of other problems including incomplete trial registration, constraints on publishing rights, withheld knowledge of adverse drug reactions, and the use of ghostwriters who were supplied by the pharmaceutical companies. CONCLUSION Financial support from a pharmaceutical company influences multiple aspects of the performance of drug trials and often leads to a favorable result for the corporate sponsor of the trial. Public access to trial protocols and results must be ensured. Moreover, more effort should be made to carry out drug trials independently, without the financial support of pharmaceutical companies.

Immunophenotypic and clinical features of T‐cell receptor γδ+ T‐lineage acute lymphoblastic leukaemia

The immunophenotypic and clinical features of TCR‐γδ+ T‐lineage acute lymphoblastic leukaemia (T‐ALL) were prospectively analysed in 52 children with membrane CD3+ T‐ALL. We observed a relatively high incidence of TCR‐γδ+ T‐ALL (26/52 patients). Leukaemic blasts from 22 children demonstrated TCR‐αβ positivity, and simultaneous expression of the TCR‐β and ‐δ chain was found in four children. Clinical and haematological features of TCR‐αβ and γδ+ T‐ALL did not differ significantly, except that haemoglobin levels were significantly lower in TCR‐γδ+ cases. Event‐free survival at 4 years was significantly better in TCR‐γδ+ compared with TCR‐αβ+ T‐ALL, but expression of TCR molecules did not emerge as an independent prognostic factor in multivariate analysis.

Klinische Studien in der Onkologie – Defizite und Lösungsvorschläge

Various investigations have identified deficits in clinical studies conducted for the market authorisation of haematological and oncological drugs. Based on data from European Public Assessment Reports (EPAR) of the European Medicines Agency (EMA), an analysis of the quality of these studies, which serve as the basis of marketing authorisation of currently approved drugs, is showing improvement. For example, endpoints recommended by the EMA are frequently used. However, deficits of marketing authorisation studies are still noticeable, e. g., results based on unplanned interim analyses or post hoc subgroup analyses. In addition to the improved quality of studies prior to marketing authorisation, independent clinical studies need to be conducted after marketing authorisation has been obtained, a good example of which are therapy optimisation studies (TOS) in acute lymphatic leukaemia (ALL). A goal of TOS is the examination of multimodal therapy concepts in the real world context of routine clinical practice. They can supply valuable data for drug safety and long-term observation. In order to conduct post-marketing authorisation studies, funding is required and bureaucratic hurdles associated with the 12(th) amendment to the Pharmaceutical Act will have to be reduced. The results of these studies are needed to efficiently handle limited health resources and to adequately inform and treat patients.

Publikationsbias in Abhängigkeit von der Art der Finanzierung bei klinischen Studien

Zusammenfassung Als Publikationsbias bezeichnet man die verzerrte Datenlage in wissenschaftlichen Zeitschriften, die dadurch entsteht, dass Studien mit positiven und signifikanten Ergebnissen eine grosere Chance haben, publiziert zu werden, als Studien mit negativen und nicht signifikanten Ergebnissen. Er hat bei durch pharmazeutische Unternehmen finanzierten Studien ein betrachtliches Ausmas. Untersuchungsergebnisse zeigen, dass teilweise mehr als die Halfte der Studien, die fur die Zulassung eines Arzneimittels von pharmazeutischen Unternehmen durchgefuhrt werden, unveroffentlicht bleiben. Auserdem wurden in diesen Untersuchungen multiple Publikationen derselben Ergebnisse, das selektive Publizieren von ausgewahlten Daten einer Studie und das Zuruckhalten von Daten zu unerwunschten Arzneimittelwirkungen aufgezeigt. Unklar ist, ob sich die Wahrscheinlichkeit fur eine Publikation bei durch pharmazeutische Unternehmen finanzierten Studien von nicht durch pharmazeutische Unternehmen finanzierten Studien unterscheidet. Auch zum Zusammenhang zwischen der Art der Finanzierung klinischer Studien und der Dauer bis zur Publikation der Ergebnisse liegen unterschiedliche Daten vor. Zum Wohl der Patienten mussen alle an klinischen Studien Beteiligte Verantwortung ubernehmen und den Zugang zu allen Daten sicherstellen.

Neue Arzneimittel in der Onkologie: Merkmale klinischer Zulassungsstudien und Argumente für die rasche Durchführung unabhängiger klinischer Studien nach der Zulassung

Die Zulassung bzw. Indikationserweiterung für alle onkologischen Arzneimittel erfolgt heute in Europa basierend auf der Verordnung (EG) Nr. 726/2004 in einem zentralisierten Verfahren der European Medicines Agency (EMA). Untersuchungen der letzten Jahre haben Mängel in den Zulassungsstudien aufgezeigt. So werden beispielsweise die Vorgaben der EMA nicht immer konsequent beachtet und Studien werden nach Zwischenanalysen, die zu diesem Zeitpunkt eine bessere Wirksamkeit gegenüber dem Vergleichsarm zeigen, vorzeitig abgebrochen. Unsere aktuelle Auswertung der Europäischen Bewertungsberichte (Auswertungszeitraum: 01.01.2009 bis 13.08.2012) zu 29 Wirkstoffen für 39 onkologische Indikationen ergibt, dass sich die Qualität der Zulassungsstudien in verschiedener Hinsicht verbessert hat. So wurden meist die von der EMA und der Food and Drug Administration (FDA) empfohlenen primären Endpunkte - Gesamtüberleben und progressionsfreies Überleben - verwendet und nur eine Studie wurde als Phase-II-Studie ohne Vergleichsarm durchgeführt. Demgegenüber werden die onkologischen Arzneimittel zur Behandlung seltener Leiden (Orphan Drugs) auf der Basis von kleinen Studien zugelassen, die vielfach offen und nicht randomisiert durchgeführt werden und Surrogatendpunkte unter suchen. Nach der Zulassung ist für die Beantwortung der noch offenen patientenrelevanten Fragen die Durchführung von unabhängigen klinischen Studien erforderlich, für die verstärkt öffentliche Gelder bereitgestellt und bürokratische Hürden abgebaut werden müssen. Nur so kann ein effizienter Umgang mit begrenzten Gesundheitsressourcen ermöglicht und die Versorgungsqualität von Tumorpatienten verbessert werden.The market authorisation or extension of indication for all oncology drugs in Europe is now based on Regulation (EC) No. 726/2004, a centralised procedure of the European Medicines Agency (EMA). Studies in recent years have highlighted deficiencies in pivotal studies. For example, the requirements of the EMA are not always consistently followed and studies are stopped prematurely after only interim analysis that at this time point shows improved efficacy with regard to the comparator arm. Our current analysis of the European Assessment Reports (reporting period: 01/01/2009 to 08/13/2012) on 29 drugs for 39 oncology indications shows that the quality of the trials for market authorisation has improved in several respects. Primary endpoints recommended by the EMA and the Food and Drug Administration (FDA) such as overall survival and progression-free survival are used, and only one study was conducted as a phase II trial with no comparator arm. In contrast, oncology drugs that are approved for the treatment of rare diseases (orphan drugs) are based on small studies which are often carried out without blinding, are not randomised and investigate surrogate endpoints. To answer patient-relevant issues following market authorisation, it is necessary to conduct independent clinical studies. Increased public funding needs to be provided and bureaucratic hurdles have to be reduced. Only this will permit a more efficient use of limited health care resources and allow to improve the quality of care for cancer patients.

Interessenkonflikte und Arzneimittelstudien – Einfluss der pharmazeutischen Industrie und daraus resultierende Gefahren für die Integrität der medizinischen Wissenschaft

Zusammenfassung Zahlreiche Untersuchungen haben detailliert das Ausmas und die Konsequenzen finanzieller Verbindungen zwischen pharmazeutischen Unternehmen, akademischen Institutionen und Arzten in der biomedizinischen Forschung beschrieben. Ausgehend von diesen Untersuchungen wurden Handlungsempfehlungen zum Umgang mit Interessenkonflikten erarbeitet, die dem Primat des Patientenwohls bei allen Interaktionen zwischen Arzten und pharmazeutischer Industrie Prioritat einraumen. Die Deklaration moglicher Interessenkonflikte und strikte Beachtung dieser Handlungsempfehlungen sind erforderlich, um Glaubwurdigkeit, Reputation und professionelle Autonomie der Arzte zu bewahren. Eine starkere Transparenz bei der Durchfuhrung und Auswertung klinischer Arzneimittelstudien sollte genutzt werden, um eine Beeinflussung klinischer Studien und tendenziose Empfehlungen zur Verordnung von Arzneimitteln zu erkennen und zu vermeiden.

SchwerpunktKlinische Studien in der Onkologie – Defizite und LösungsvorschlägeClinical trials in oncology: deficits and proposals for solution

Various investigations have identified deficits in clinical studies conducted for the market authorisation of haematological and oncological drugs. Based on data from European Public Assessment Reports (EPAR) of the European Medicines Agency (EMA), an analysis of the quality of these studies, which serve as the basis of marketing authorisation of currently approved drugs, is showing improvement. For example, endpoints recommended by the EMA are frequently used. However, deficits of marketing authorisation studies are still noticeable, e. g., results based on unplanned interim analyses or post hoc subgroup analyses. In addition to the improved quality of studies prior to marketing authorisation, independent clinical studies need to be conducted after marketing authorisation has been obtained, a good example of which are therapy optimisation studies (TOS) in acute lymphatic leukaemia (ALL). A goal of TOS is the examination of multimodal therapy concepts in the real world context of routine clinical practice. They can supply valuable data for drug safety and long-term observation. In order to conduct post-marketing authorisation studies, funding is required and bureaucratic hurdles associated with the 12(th) amendment to the Pharmaceutical Act will have to be reduced. The results of these studies are needed to efficiently handle limited health resources and to adequately inform and treat patients.

Offene Fragen in der medikamentösen Tumortherapie mit neuen Wirkstoffen

Zum Zeitpunkt der Zulassung bzw. der Indikationsausweitung neuer onkologischer Arzneimittel ist es oft nicht möglich, den für den Patienten relevanten Nutzen verlässlich abzuschätzen, da sich die Konzeption der klinischen Studien, auf denen die Zulassung bzw. Indikationsausweitung basiert, in erster Linie an den regulatorischen Anforderungen der Zulassungsbehörden orientiert. Darüber hinaus wird eine unabhängige Bewertung von Wirksamkeit und Sicherheit neuer onkologischer Wirkstoffe dadurch erschwert, dass Ergebnisse der Zulassungsstudien häufig nur unvollständig oder erst einige Zeit nach Abschluss der klinischen Studie(n) publiziert werden. Die Klärung noch offener, für die individuelle Behandlung von Patienten relevanter Fragen erfordert deshalb die Durchführung unabhängiger, wissenschaftsinitiierter klinischer Studien nach der Zulassung. Für die Durchführung derartiger Studien fehlen jedoch meist die finanziellen Mittel. Außerdem werden sie durch regulative und akademische Rahmenbedingungen behindert. Weitere Herausforderungen der medikamentösen Tumortherapie resultieren aus den sehr hohen Kosten für neue onkologische Therapien, die in einer alternden Bevölkerung mit steigender Prävalenz von Tumorerkrankungen die Ressourcen der gesetzlichen und privaten Krankenversicherung (GKV, PKV) stark belasten. Die Durchführung unabhängiger klinischer Studien nach der Zulassung muss sichergestellt werden, um eine bedarfsorientierte und effiziente Behandlung mit neuen onkologischen Wirkstoffen zu gewährleisten. Neue Perspektiven ergeben sich für die Kostenerstattung bei innovativen onkologischen Therapien, wenn z.B. die Kostenübernahme durch die GKV und PKV an die Evidenzgenerierung im Rahmen klinischer Studien koppelt und dadurch die Versorgungsqualität von Tumorpatienten verbessert sowie ein effizienter Umgang mit begrenzten Gesundheitsressourcen ermöglicht wird.