Qualität bei klinischen Studien – Mehr Training ist der falsche Reflex

Die Qualität klinischer Prüfungen wird in erster Linie durch den Sponsor, den Monitor, den Prüfer – gelegentlich auch durch den Patienten bestimmt. Der Sponsor ist verantwortlich für die Qualität des Prüfplans, die Auswahl, Schulung und Arbeit der Monitore, vor allem aber durch die Auswahl der Prüfer.

Handelt es sich um Parameter, auf die der Patient einen Einfluss hat, etwa ein Tagebuch, so ist die gewissenhafte Ausführung eines solchen für die Qualität der Prüfung essenziell. Wird etwa ein Prüfer ausgewählt obgleich man an seiner Zuverlässigkeit Zweifel hat, so ist dies selten durch verstärktes Monitoring zu kompensieren.

Auch die verstärkte Verwendung von Audits kann zwar Fehler erkennen, sie aber selten beheben, geschweige denn einen für die gegebene Studie effektiven Lernzyklus in Gang setzen. Wie häufig und wie intensiv das Monitoring durchzuführen ist, lässt sich auch heute nicht klar sagen.

Auch wenn für die Existenz des Patienten, die Einschluss- und die Ausschlusskriterien sowie die schwer wiegenden unerwünschten Ereignisse ein Vergleich mit der Quell Dokumentation durchgeführt wird, so ist damit noch keine Garantie für die Qualität gegeben.

Sinnvoll ist sicher, innerhalb von ein bis zwei Wochen nach Einschluss des ersten Patienten eine Kontrolle durchzuführen, um die Wiederholung von Fehlern zu vermeiden. Ob danach im Rhythmus von vier, 6,8, oder 12 Wochen monitoriert wird, hängt von der Anzahl der Patienten sowie den Befunden bei der ersten Kontrolle ab.

Ein Verfahren zur Steuerung der Qualität können Inspektionen der Behörden hingegen kaum sein, da sie spät durchgeführt werden und da deren Empfehlungen und die Umsetzung derselben für die Studie oft keine Relevanz mehr hat. Jedoch lassen sich aus den Befunden solcher Inspektionen Änderungen von Prozessen und Kontrollverfahren ableiten, die späteren Studien zugute kommen.

Bei den meisten Sponsoren spricht man noch immer nicht von einem Qualitätsmanagement, sondern von einer Qualitätssicherung, oft nicht einmal von einer Qualitätskontrolle. Gerade aber die Kontrolle laufender Prozesse ermöglicht es, Fehler bereits im Keim zu erkennen und auszumerzen. Das Qualitätsmanagement sollte zwar in einer von der klinischen Forschung unabhängige Einheit laufen aber in engem Dialog mit dieser sein.

Neben den üblichen Audits empfehlen sich auch Selbstinspektionen, bei denen die reale Durchführung von Aktivitäten, anhand derer Kriterien des Qualitätsmanagements überprüft werden. Wie weit SOPs dabei helfen können und wo das Optimum in der Zahl und in Detaillierungsgrad liegt, ist weiterhin unklar. Sicher ist nur: SOPs, die in großen Mengen auf die Anwender nieder prasseln, werden kaum gelesen, und dabei könnte gerade die essenziellen Regeln für eine Qualität der Prozesse vernachlässigt werden.

Wenn wir das Monitoring als einen Zyklus betrachten, bei dem der Monitor Fehler und Probleme aufdeckt, dokumentiert, weiter meldet oder selbst erhebt, und aus diesem lernen eine bessere Form des Monitoring resultiert, dann lohnt es sich, die Elemente dieses Prozesses, wie sie heute bei den meisten Studien gefunden werden, näher zu betrachten. Zum einen ist die Fähigkeit des Monitors, Probleme zu sehen, gegebenenfalls auch Betrug aufzudecken und die Mitarbeiter an der Prüfstelle darauf hinzuweisen und sie zu trainieren, eine Grundvoraussetzung. Werden aber Probleme nicht dokumentiert, Lösungsansätze nicht beschrieben, Zeiten zur Lösung der Probleme nicht festgelegt und ungelöste Probleme rigoros nachverfolgt, so haben wir hier die erste Schwachstelle.

Reagiert der Projektleiter des Sponsors nicht auf die Meldung des Monitors – weil er es übersieht, nicht für wichtig hält oder überlastet ist – so ist eine zweite Schwachstelle rasch identifiziert. Beim Sponsors selbst sollten Befunde in der einen klinischen Prüfung so kommuniziert werden, dass vergleichbare Fehler in anderen Studien vermieten oder rasch kompensiert werden.

Dies gilt auch für Audits, deren Ergebnisse rasch kommuniziert werden müssen und in Training umzusetzen sind – ein jährliches Qualitätshandbuch kostet nur Papier und ist für den Lernzyklus unerheblich. Bei Problemen in der Qualität findet sich zunächst der Ruf nach zusätzlichen Training, auch wenn der Erfolg des Trainings nicht einmal unmittelbar nach dem selben, etwa durch einen einfachen Test, gemessen wird. Häufig wird das Training auch für die gesamte Gruppe etwa für alle Monitore für notwendig gehalten, so dass einerseits alle das Training durchführen müssen, andererseits keine Zeit für eine intensive Schulung derer übrig bleibt, die es tatsächlich nötig haben. Oft wird auch davon gesprochen, dass die Mitarbeiter an der Prüfstelle zusätzliches Training brauchen, um Fehler zu vermeiden.

Analysiert man die meisten Fehler bei klinischen Prüfungen so stellt man fest, dass sie sich auf einige wenige Punkte kondensieren lassen: fehlerhafte Aufklärung der Patienten, unvollständige oder verspätete Dokumentation schwer wiegender unerwünschter Ereignisse, unsachgemäßer Umgang und Dokumentation mit dem Prüfmustern, mangelnde Aufsicht des Hauptprüfers über die anderen Mitarbeiter der Prüfstelle. Fragt man die Mitarbeiter nach dem Grund für die Verletzung der Regeln so wird wahrheitsgemäß selten geantwortet, dass man diese nicht gekannt habe, sondern dass man dies einfach vergessen oder übersehen habe. Oft ist das vergessen eine Chiffre für Nachlässigkeit und Schlamperei. Man könnte einwenden, dass man die Qualität durch entsprechende vertragliche Vereinbarungen besser dingfest machen können. Dabei wird nicht berücksichtigt, dass der Inhalt der Verträge nach deren Unterschrift selten angeschaut wird und dass die meisten Sponsoren auch bei Verletzung von Qualitätskriterien keine Konsequenzen, insbesondere keine finanziellen, einleiten.

Selbst wenn keiner der Patienten auswertbar ist, wird das Prüferhonorar nur selten zurückgefordert. Selbst bei nachgewiesenem Betrug scheuen sich viele Sponsoren, strafrechtliche Schritte auch nur in Erwägung zu ziehen. Da in Deutschland anders als in den USA keine Liste gesperrter Prüfer existiert, wodurch eine gewisse Generalprävention möglich ist, müssten solche Maßnahmen auf der Ebene der Prüferverträge festgeschrieben werden.

Man könnte sich vorstellen, dass die Ethik-Kommission immer dann informiert wird, wenn bei Audits kritische Befunde aufgetreten sind oder wenn schwer wiegende Verstöße gegen GCP festgestellt wurden. Auch die Rückforderung von Gelder, wenn dies unter Prüfern bekannt wird, könnte präventiv zu einer höheren Qualität der Daten und auch zu einem besseren Schutz der Patienten führen. Damit soll nicht einer absoluten Qualität das Wort geredet werden. Eine solche absolute Qualität, wie sie etwa in den Begriffen vom Six Sigma auftaucht, ist bei klinischen Prüfungen weder notwendig noch möglich. Klinisch relevante Unterschiede sollten so robust sein, dass auch ein geringer Prozentsatz an mangelhaften Daten den Unterschied zu Placebo nicht zunichte macht. Bisher allerdings scheuen sich Behörden wie Sponsoren an die Definition der akzeptablen Qualität heranzugehen. Mangelhafte Qualität darf nicht dadurch entschuldigt werden, dass Prüfpläne und die Logistik einer klinischen Prüfung nicht selten komplexer als nötig und somit störanfällig sind.

Dennoch ist die Verantwortung des Sponsors für einfache und unmissverständliche Prüfpläne und für eine die Prüfstelle nicht überfordernde Logistik klar. Nicht funktionierende Randomisierungssysteme, langsam sich aufbauende Bildschirmseiten bei elektronischer Dateneingabe, versagende e-diaries beim Patienten oder unzuverlässige Laborärzte oder Pathologen oder mehrfache Rückfragen zu bereits beantworteten Unklarheiten sind vermeidbar und daher nicht hinnehmbar. Bei allen Reden über die Qualität klinischer Prüfungen sollte nicht vergessen werden, dass dies geschieht, um Patienten zu schützen und auswertbare Daten zu erhalten. Vieles, was heute bei Studien etwa im Antrag für die Ethikkommissionen gefordert wird, geht weit darüber hinaus. Dass ein Arzt zwei Tage brauchen soll, um GCP zu lernen, ist die Vermutung von Individuen. Dass solches Lernen nur in Präsenzveranstaltungen geschehen kann, ist ein Märchen: ein gutes e-learning mit einer Lernkontrolle ist dem absitzen eines Seminars sicher überlegen. Auch das Selbststudium sollte eingefordert werden – auch die übrige ärztliche Fortbildung lässt dies zu und erfordert es.

Das KliFo Buch – 3. Auflage jetzt verfügbar

Hervorgehoben

Klinische Forschung mit Erfolg
Projektmanagement, juristische und regulatorische Aspekte, konkrete Durchführung von Studien – in diesem Praxisbuch finden Sie alles, was Sie über klinische Forschung wissen müssen!
Von der Idee bis zur abschließenden Analyse und Veröffentlichung werden sämtliche Schritte klinischer Studien mit fundiertem Know-how und vielen praktischen Anleitungen, aber ohne komplizierte Mathematik erklärt. Ein Fokus liegt auf häufig auftretenden Problemen und zeigt Ihnen Wege auf, diese zu lösen.
Die 3., vollständig aktualisierte Auflage berücksichtigt die 16. AMG-Novelle einschließlich der Änderungsgesetze und der daraus resultierenden Veränderungen hinsichtlich der neuen EU-Verordnung. Auch PASS – und PAES-Studien sowie das Thema risikoadaptiertes Monitoring (Risk-based-Monitoring) sind hinzugekommen.
Für Ärzte und Naturwissenschaftler, die in Kliniken, Praxen, pharmazeutischen Unternehmen und Auftragsforschungsinstituten tätig sind, ist das Das KliFo-Buch der ideale Kompass bei der Realisierung von interventionellen wie nichtinterventionellen Studien sowie bei der Entwicklung von Diagnostika und diagnostischen Verfahren.

Das Downloadmaterial steht auf dieser Seite zur Verfügung. Ausgewählte Aktualisierungen werden auch über diese Seite veröffentlicht.

Alle im Buch angegebenen nützlichen Links au dem Kapitel 7 stehen ebenfalls zur Verfügung.

De-SOPing the industry – Michael Herschel

Michael Herschel D-SOPing the industry
Herschel’s Heresies
Under guidance from regulatory agencies and through interpretation of guidelines and directives, the pharmaceutical industry has developed sets of standard operating procedures (SOPs) against which auditing takes place. The justification for SOPs is not only to quantify procedures during trial conduct but also to meet the requirements raised in ICH-GCP, which states that such SOPs should be written and adhered to. The ICH-GCP documents do not stipulate the minimum content of such SOPs, however, it could be deducted that all procedures that directly affect either the protection of study subjects or the integrity of study data should be harmonised in this way.

Although concise, the above introduction could help determine when SOPs are needed and they are not, i.e. when simple procedural descriptions would suffice. In the beginning, SOPs where meant to reflect best practice, however, nowadays it is more usual that specialised personnel write SOPs – very often without previous practical exposure to the very procedures they are describing. One could object that, in learning companies, SOP development could in fact be preventing progress because changing SOPs is very difficult and politically incorrect as there is always the suspicion that simplifying SOPs may result in reduced quality. I know of no case where a reform of SOPs resulted in a significant reduction of either individual SOP length or number – by eliminating the SOPs that would be better replaced with procedure descriptions, which are much more amenable to improvements in process quality.

This is especially true for global companies in which SOPs are usually maintained on a worldwide basis and, thus, are even more difficult to change compared to smaller companies. If one takes the example of monitoring visit intervals, one can see the wide interpretation of what ICH-GCP says. In some companies four weeks is described in eight, in others an “adequate interval” is considered sufficient. I assume that this reflects the desire of ICH-GCP for high quality monitoring (and I may assume that all of them achieve this, probably with slight differences in cost and resource consumption).

It is frequently current practice to issue new or revised SOPs at seemingly random intervals, which intensifies training schedules and forces people to spend much time re-learning. Policies to reduce new issuance of SOPs to what is necessary (to accommodate changes in the legal sphere, for example) to twice or, at the most, four times a year would require that a new SOP should not be longer than its predecessor and that any new SOP must be accompanied by the elimination of an old one. This would be a good first step towards thinning out the SOP “jungle”, which can currently only be survived with a knife capable of cutting through the SOP book.

Another solution to the problem would be to reduce the number of clinical compliance SOP writers by fifty percent. I am sure that such a measure would not reduce the quality of the SOPs because quality is usually dependent on good practice in the field, and this is the responsibility of the clinical research heads.

Let me make some final suggestions. First, members of a SOP department should have sufficient practice of the very procedures on which they are writing and, more importantly, they should not stay longer than five years in a SOP department before having to return to “active duty”. Secondly, they should reduce their SOPs to a minimum in order to enable better use of the brains and motivation of intelligent employees who, if managed well, will find the best procedures for both the protection of subjects and the integrity of data.

If one takes an analogy of what we currently live through then one may return to the dispute of 19th century European military logic. On the one hand the British and Prussian armies relied heavily on the decision making ability of their people on the front line – thus reducing incompetence and red tape while, on the other side, the majority of the remaining continental armies were doing just the opposite and leading by what we now refer to as micro-management. The jury is delayed about which is the better tactic; however, we want neither new wars nor inefficient clinical research.

(C) 2008 – Alle Rechte vorbehalten

Exit strategies for stratgic sourcing – Michael Herschel

For those that are devoted to strategic outsourcing such articles may be a taboo, similar to a marriage contract. Yet, in uncertain times, it is wise to anticipate when partnerships break up. Where is the fatal flaw? The flaw is that many consider a strategic partnership not as normal business relations, but as something more “cosy” and even as being of a higher moral quality. Let us therefore get started with how strategic partnerships come into being!
The questions at the start should be:
1. Why do I go for strategic outsourcing? Would tactical outsourcing do the job, with a limited number of preferred providers?
2. Have I had extensive experience with the chosen partners, over several studies, in much more than one area of outsourcing, and has this been very satisfying both at corporate and the affiliates?
3. Will I have one, two or more strategic partners? I suggest at least 4 as this reduces the workload that may have to be taken over or redistributed, to 25%.
4. Will I keep a certain level of functional outsourcing – with extra partners? If they are capable, this could reduce my dependency.
5. Will I have internal capacity that is not only able to supervise the strategic partner but also knows in detail the kind of work the strategic partner does?
6. For how many years will my initial contract run? I suggest between 3 and 6.
7. What percentage of my work will I outsource – on a trial and a number of patients basis?
8. How do I minimize vulnerability? What will happen if I have a major problem during a pivotal trial program?
9. Am I able to cancel the partnership and transition the work within a maximum of four weeks? If you are not you should not strategically outsource.
Let us hope that this list does not encourage you from strategic outsourcing. It does make sense provided you make the above precautions. Now you made your contracts, you executed them, until you found that this is not your optimal style of working, economically or else. Or the CRO partner ran into a major quality problem, pushed the fees or behaved in an unacceptable way. Or you did, and your partner got annoyed.
Let us assume the contract was correct, and you reserved your right for exits of some kind.
What need to be considered for an exit strategy?
1. Make sure there are no legal problems left.
2. Have an internal plan ready which can be made to purpose and is ready to be executed now.
3. For each activity have a plan how it can be transitioned to you or another vendor.
4. Form an internal “battle group” that oversees the transition, of the major areas that are concerned. Appoint a new project leader immediately, best the person who was the main contact if this is desirable.
5. Inform all stakeholders about the split and how you will go ahead. Make sure authorities, ethics committees, and investigators know early and do not fall into a panic.
6. Document all findings which could mean that the contract has not been honored in full.
7. Revise the budgets allowing a final bottom line with the previous business partner, and a new budget for the new ways of working. Make sure other vendors receive their payments in time.
8. Make a particular analysis of the patient protection issues and of data quality. Hope you included respective penalty payments in your contracts.
Finally ….
Finally let us hope you never need this advice. But as the old Romans said:
Si vis pacem, para bellum (if you want peace, be also prepared for war).

CROs – Is the sun rising or …. – Michael Herschel

Michael Herschel Is the sun rising or …..
Herschel’s Heresies
Synopsis
Contract Research Organisations (CROs) have enjoyed a positive change in pharmaceutical outsourcing policy, which coupled with a rise in the number of patients per NDA has further supported current success. In his two-part article, Herschel submits his CRO situation analysis and refers to changes within the pharmaceutical sector that may have a big impact on their future.
The development of CRO’s
In the past ten years, more and more pharmaceutical companies have outsourced part of their clinical trial programmes. Although originally employed to minimise peaks in internal resource requirements, the percentage of outsourcing has grown to the extent whereby it now exceededs 50% of the total workload in some companies. Smaller companies have used CROs in order to save building-up internal clinical trial expertise prior to reaching a critical mass. In addition, recent years have seen a rise in the number of patients per NDA and consequently a proportionate rise in the number of patients per clinical trial programme. Thus, CROs have been able to seize an increasing share of this market. They have also followed in the footsteps of pharmaceutical companies and used mergers and acquisitions to strengthen their market position. Today, just five CRO’s control over 50 % of the market.
Most CROs offer “full services” management, with very few focusing on “indication” or “specialist” services such as data management or programme planning. However, some companies have recognised a need to attract subcontractors and have moved to integrate subcontractors into their companies to enhance their service profiles.
The value proposition of CRO’s
Contract Research Organisations, like business consultants, usually advertise themselves as having “a major group of clients”. They often state that their learning curve is much steeper and also claim to bring a variety of experiences to a trial compared with that procured by a single company – especially one that has experienced little fluctuation within its clinical research department.
In contrast, it appears that staff turnover within the CRO sector is considerably higher than that experienced by pharmaceutical companies. This is mainly because most personnel would prefer to join a pharmaceutical company, which they perceive to be able to offer more job security than a CRO can. Therefore, CROs have to spend a larger proportion of their money on education and training.
In a survey that we conducted to assess the performance of CROs, we did not find them to be faster, or more cost effective than drug companies. The survey found no difference in data quality either. This may not come as a surprise – one reason being that CRO deployment is often used to save potentially idle personnel, which is a consequence of the fluctuations incured by one’s drug pipeline.
It appears that one of the special properties proffered by CROs is their presence in countries in which pharmaceutical companies are not. This is of particular importance to pharmaceutical companies that do not wish to build up their own research departments in certain countries. It is also of service to smaller pharmaceutical companies that cannot be present in various countries for financial reasons.
Outsourcing criteria
In presentations CROs like to discuss different outsourcing tactics and strategies. Contract Research Organisations consider tactical outsourcing to be less desirable as it means irregular employment, which is tendered according to cost. CRO’s usually prefer strategic alliances, which represent more security and so enables them to build up more competencies with the aim of achieving preferred provider status.
Decision of outsourcing
The decision to outsource clinical trials is usually based on a cost/benefit calculation. While in some cases the sheer absence of skilled personnel may force a company to outsource parts of the drug development process, it is usually because of the cost implications. Keeping a large and inflexible clinical research department makes less business sense. In some cases key departments prefer to maintain a low headcount and, hence, a reduced level of outsourcing. However, this may not have a positive affect on the cost base mid- and long-term.
(C) 2008 – Alle Rechte vorbehalten

Clinical trials that fail before they start. Practical view from a sponsor – Michael Herschel

There are trials where experienced clinical research experts have a bad gut feeling even before the first patient has been enrolled. There may be an excellent statistician, a famous group of key opinion leaders endorses the trial, regulatory agencies like it – but it becomes a never ending story finding patients for it.
The magic triangle of speed, quality, and cost needs to be changed into a square by adding human nature. Human traits here may have some consequences. Misanthropic Schopenhauer would see the dire consequences only:
Optimism – few centres will do it
Habits – keep those eligibility criteria that worked in phase II
Selective listening – but: they will try although they seem to fail to enrol
Grandeur – maximise it all at once, after all you are the leader
Linear thinking- if this is so I shall have to bow
Other traits, Rousseau might have remarked, create opportunities:
Curiosity – new ways of recruitment
Sports spirit – performance listings
Grace under pressure – last minute amendments
Community – investigator idea exchange
Sharing – financial support for study nurse
In preparing for a trial, feasibility is an often used phrase but is hardly done meticulously. It does start with a critical look at the protocol. Frequently, limiting patient eligibility starts with recruitment. Among the most frequent pitfalls are
– Excluding patients above a certain age, e.g. above 65 years of age
– Excluding women
– Excluding related disease even if the primary endpoint is applicable to them as well
More problems arise with exclusion criteria. Their choice is often based on obtaining a clinically pure population, with no concomitant disease and no other drugs taken regularly. Frequently used exclusion criteria whose wisdom may be questioned are
– Inability to co-operate (who knows ?)
– Intake of acetyl salicylic acid preparations
– Relevant cardiovascular, hepatic or renal disease (so what is “relevant”)
– Previous diagnosis of cancer (even if resolved…)
– Known allergies
The multitude is the more problematic as it not only limits the number of patients like a type of funnel, but has a negative impact on the drug approval labelling and prevents the sponsor from gaining knowledge in important patient populations before registration. In some cases the limitation, especially in phase II of clinical development, is reasoned for by reducing variability, however, there is no published evidence that “opening up” the patient population increases the variability of the primary endpoint and thus may lead to larger sample size.
Most often, feasibility is understood as the feasibility of the investigator site. According to ICH Good Clinical Practice, it is the task of the sponsor to ensure that the site is able to do the study. Even at renowned companies this meant to ask the investigator whether he would be able to come up with x randomised patients in y months. Temptingly, the answer was frequently “yes”, and this led to building, as the “yes” may have looked less credible, so-called contingency plans. Only recently it has been established practice in several companies to
– Ask for historical data, listing real patients from pre-specified past period, who would have been eligible, possibly with a disease characteristic that could even allow to calculate real variability of the endpoint (e.g. haemoglobin A1c)
– Set a time for the investigator to give feedback (as a knock-out criterion)
– Divide the number given by a figure between 2 and 6, depending on the difficulty of the study and the task to convince patients to participate
Yet, the mistakes of the past are still committed:
– Taking mostly key opinion leaders
– Taking the numbers given for granted
– Paying for feasibility data
– Believing in “centres of excellence” (who may have been good in the past…)
There are feasibility factors much less considered though their impact is high:
– Time to obtain an ethics committee vote
– Time to obtain trial permits (thanks to the European Directive, all of Europe but Italy will become slower now)
– Referral patterns or “who has got the patients for diagnosis, and who for treatment”
– Limited resources at the site even if not competing for the same patient group
– Investigator ready to move house or going on a sabbatical
– Time to completing the contract with the centre (mostly a problem in hospitals)
Finding the right investigator fee is yet another difficulty to overcome. The Scylla of too low fees, often bordering on “unfair” market value is facing, on the other side, the Charybdis of fees that may be spoiling investigators, or what is worse, be seen as an attempt to corrupt institutions. Clearly only those ,measures should be paid that exceed standard treatment cost. However, it may be necessary to use an database such as PICAS (Data Edge, Inc.) for comparisons. And, some studies may be necessary for approval, but boring enough so that only monetary inducement may lead to satisfying recruitment speed and quality.
In a time of shortening recruitment lines, contingency plans are now mostly based on good feasibility data and sound planning. Recruiting extra centres many months after the start of a trial is no longer viable. It is needed to define for each trial the “last intervention point”, i.e. the date after which no “fire brigade work” would salvage the recruitment time any more.
Therefore we suggest the following practical advice:
– Plan each study with (more than) sufficient centres
– Do not think you save money by restricting drug supplies or other trial materials
– Train investigators how to convince a patient to participate in a trial
– Make every trial as representative of the real patient population as you can by
eliminating exclusion criteria and being liberal with inclusions
More problems arise with exclusion criteria. Their choice is often based on obtaining a clinically pure population, with no concomitant disease and no other drugs taken regularly. Frequently used exclusion criteria whose wisdom may be questioned are
– Inability to co-operate (who knows ?)
– Intake of acetyl salicylic acid preparations
– Relevant cardiovascular, hepatic or renal disease (so what is “relevant”)
– Previous diagnosis of cancer (even if resolved…)
– Known allergies
The multitude is the more problematic as it not only limits the number of patients like a type of funnel, but has a negative impact on the drug approval labelling and prevents the sponsor from gaining knowledge in important patient populations before registration. In some cases the limitation, especially in phase II of clinical development, is reasoned for by reducing variability, however, there is no published evidence that “opening up” the patient population increases the variability of the primary endpoint and thus may lead to larger sample size.
Most often, feasibility is understood as the feasibility of the investigator site. According to ICH Good Clinical Practice, it is the task of the sponsor to ensure that the site is able to do the study. Even at renowned companies this meant to ask the investigator whether he would be able to come up with x randomised patients in y months. Temptingly, the answer was frequently “yes”, and this led to building, as the “yes” may have looked less credible, so-called contingency plans. Only recently it has been established practice in several companies to
– Ask for historical data, listing real patients from pre-specified past period, who would have been eligible, possibly with a disease characteristic that could even allow to calculate real variability of the endpoint (e.g. haemoglobin A1c)
– Set a time for the investigator to give feedback (as a knock-out criterion)
– Divide the number given by a figure between 2 and 6, depending on the difficulty of the study and the task to convince patients to participate
Yet, the mistakes of the past are still committed:
– Taking mostly key opinion leaders
– Taking the numbers given for granted
– Paying for feasibility data
– Believing in “centres of excellence” (who may have been good in the past…)
There are feasibility factors much less considered though their impact is high:
– Time to obtain an ethics committee vote
– Time to obtain trial permits (thanks to the European Directive, all of Europe but Italy will become slower now)
– Referral patterns or “who has got the patients for diagnosis, and who for treatment”
– Limited resources at the site even if not competing for the same patient group
– Investigator ready to move house or going on a sabbatical
– Time to completing the contract with the centre (mostly a problem in hospitals)
Finding the right investigator fee is yet another difficulty to overcome. The Scylla of too low fees, often bordering on “unfair” market value is facing, on the other side, the Charybdis of fees that may be spoiling investigators, or what is worse, be seen as an attempt to corrupt institutions. Clearly only those ,measures should be paid that exceed standard treatment cost. However, it may be necessary to use an database such as PICAS (Data Edge, Inc.) for comparisons. And, some studies may be necessary for approval, but boring enough so that only monetary inducement may lead to satisfying recruitment speed and quality.
In a time of shortening recruitment lines, contingency plans are now mostly based on good feasibility data and sound planning. Recruiting extra centres many months after the start of a trial is no longer viable. It is needed to define for each trial the “last intervention point”, i.e. the date after which no “fire brigade work” would salvage the recruitment time any more.
Therefore we suggest the following practical advice:
– Plan each study with (more than) sufficient centres
– Do not think you save money by restricting drug supplies or other trial materials
– Train investigators how to convince a patient to participate in a trial
– Make every trial as representative of the real patient population as you can by
eliminating exclusion criteria and being liberal with inclusions
(C) Michael Herschel 2008 – Alle Rechte vorbehalten