Das KliFo Buch – 3. Auflage steht kurz vor dem Druck

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.

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

Opinion Leaders in Medicine – Michael Herschel

Synopsis
This is a particularly interesting question, and one that we usually avoid because it is socially challenging. In his usual, direct manner, Herschel provokes a review of the definition of opinion leaders and departmentalises their value within clinical research and product promotion.

An Article of Faith?
What is an opinion leader?

Opinion leaders in medicine, and for the pharmaceutical industry in particular, are outstanding individuals – usually physicians who “lead the field”. By definition, an opinion leader is empowered by a group of “followers” to influence it. They are able to persuade others to accept his or her beliefs and to adopt his or her prescribing behaviour or other therapeutic methodologies that they favour. Opinion leaders can, in principle, be from all levels of medicine. In reality, however, they are usually very vocal individuals with high academic status or, at least, a high political and social status.

Concepts of opinion leadership
Political science suggests several models. There is a communication model, which is based on communication science and the dissemination of information and influence. This model is based on communication and cognitive function. It can be used to explain, among other things, the process by which medical information diffuses from its source to the parameters of the profession and how individuals can influence this process.

An alternative model is that of the “role model” as adopted by the opinion leader. From the opinion leader perspective, the role may appear functional; however, it is dependent on the acceptance of the individual within the underlying role to his or her function. In addition, the opinion leader role is one that the opinion leader enjoys and so achieves through personal attitudes and expectations as well as through action.

It is only more recently that measuring the effect of an opinion leader has started to become considered an experimental science. The results so far are disappointing; however, there are still several research projects in progress that are looking into how to convince opinion leaders, for instance.

Genesis of an opinion leader
While this may represent an entire research project, opinion leaders in medicine usually arise from leading academic institutions. As long as the cognitive model of medical science is valid, academic institutions will take this lead. However, it is not clear how strong the influence outside such institution really is if the individuals concerned are not outstanding national figures. Interestingly enough, the study of “fallen angels” ie opinion leaders that have lost their credibility and influence, shows, in most cases, that there was a point at which they “misbehaved” according to their “followers”.

What opinion leaders are good for?
According to common knowledge, opinion leaders do not necessarily have great recruitment rates on their own studies. However, if they are figures that are visible beyond their investigator circles, they can have a positive effect on patient recruitment through radio or TV appearances. They can generate great public relations, which enhances recruitment of patients onto trials. By writing favourable information about drugs in early development they can influence public opinion to bring about the desired affect.

An empirical approaches to opinion leadersIf opinion leaders can be defined by their influence on followers, questioning followers would be a logical choice. There is a difficulty though as many followers will not readily admit that they belong to the follower’s group, but like to maintain their illusion that all of their decisions relating to diagnoses and treatment are their own. Thus, more refined market research and opinion research has to be done. On the other hand, one could do so more easily by presenting a choice of potential opinion leaders to industry professions, or by them to volunteer spontaneous nominations.

Making use of opinion leaders
In general, there are four different types of situations in which you may work with opinion leaders. In the first of these “situations” your objective may be to convince an opinion leader to concede with a propagated opinion. Usually, opinion leaders are scientifically reasonable people who can be convinced by valid scientific data over (sometimes, considerable) time. It is almost impossible to influence opinion leaders without presenting appropriate evidence in support of the new opinion. Without sufficient evidence it is unlikely that the opinion leader will adhere to the opinion or its promotion.

Opinion leaders may be differentiated into two types. “Type 1” describes those more likely to actively speak in favour of a product, diagnostic tool, or therapy. “Type 2” refers to those who are more likely to remain sceptical, or even critical, towards new information. Further, Type 2 may endanger a positive image, or evidence, generated by a drug development programme. From a drug company’s perspective, the measures that are necessary to neutralise the potentially damaging effects of Type 2 opinion leaders, differ to those that are necessary to convince and persuade Type 1.

The association of an opinion leader or leaders with a trial is highly desirable, however, this role is usually one of a figurehead – as they are often too busy with other activities, such as lecturing and caring for real patients, to provide hands-on management of clinical trials.

Lastly, but mostly importantly, opinion leaders can be of tremendous value if deployed to support marketing activities. They have a wealth of experience and excellent clinical judgement in addition to usually having lived long enough not to be subject to fashion. Therefore, product support can be considered the main stay of an opinion leader’s usefulness. Needless to say, this is limited to products for which they can be “won over”.

Dangers of opinion leaders
Opinion leaders, especially conservative ones, can be extremely dangerous for the development of products. If their opposition is not addressed they can develop into enemies. On the other hand, even opinion leaders that are in favour of the product may actually use their power against the company that elected them. Therefore, it is wise to gain the support of more than one opinion leader in order to have an “insurance policy” to limit the potential damage that could result if one or other of the opinion leaders decides to support another product(s).

The right place of opinion leaders – is there one?
As discussed, the rightful place for opinion leaders is, except for the most progressive, not in the earliest stages of development but in the later stages of development or at product launch. As they are extremely vocal individuals and may have many followers, it is ideal to have them support a product in a given indication on the back of its scientific validity.

Marketing againt opinion leaders
There are examples whereby marketing against opinion leaders has not only succeeded but has actually changed the face of an indication. However, it requires that positive public opinion is courted and engaged at a level that can support a sustainable, public rebellion against opinion leaders – as can happen if extremely good scientific efficacy and/or safety evidence exists. In such cases, communication strategies will be different but should avoid irritating opinion leaders and should aim to keep them neutral, if possible.

There are several examples of communication breakdowns that occurred as a direct result of companies trying to work against opinion leaders. Communication is especially prone to breakdown when there is a significant change to paradigms as happened with the advent of the helicobacter pylori theory in peptic ulcers, for example. It took many years for this theory to emerge because most of the opinion leaders in the field at the time were not convinced by the concept and so avoided getting involved. Therefore, many attempts to market products that relied on the uptake of this theory failed because the opinion leaders were clearly supporting the incumbent products.

Having said all this, opinion leaders are very important but, in fact, we know very little about how they become opinion leaders, how they maintain their status and how to differentiate true opinion leaders from those whom we think are opinion leaders or those who think they are opinion leaders. A lot of research topics for social scientists are waiting to be tackled that should uncover some interesting results within this little known, but fascinating topic, that explores the science of personal influence.

Herschel’s Heresies

(C) 2008 – Alle Rechte vorbehalten

Market-driven pharma. Should pharmaceutical companies really be …. market-driven? – Michael Herschel

 

Should pharmaceutical companies really be ….
… market-driven?

In a big pharmaceutical company the majority of top executives are either marketing experts or other specialists that have spent some of their career in marketing. Indeed, medical advisors who wish to advance within a pharmaceutical company are usually advised not to stay in medicine for too long but rather to move into marketing and sales, or, corporate affairs or licensing and acquisitions – at the very least.

This implies that marketing is the key to commercial success. While this may be true in some cases, where some of the marketed products show little or no superiority over existing ones, for example, it is clearly easier to make a commercial success of a product that can be differentiated from others in the market place and that has a clear advantage over “me-too” products that need a lot of marketing support.

In some companies marketing dominates product research and development early on. In these companies, early developments are scrutinised for further commercial exploitation. As a consequence of traditional accounting techniques, such as net present value, they are often dismissed too early – before they have had an opportunity to demonstrate potential. Furthermore, the strategic frameworks that govern marketing plans have often originated for use in large therapeutic areas, in which there are many patients and many prescribing physicians, and so are not always appropriate for use in other areas of true therapeutic need. Looking back in history, the estimation of markets has often been incorrect and sometimes appears to be formed on a basis of wishful thinking. I can recall a recent marketing scenario that assumed that 20% of all American women suffer from a disease called “sexual hypofunction” – without any medical evidence or data in support of this assumption. I sometimes wonder whether the determination of incidence and prevalence of diseases should not be left to medical experts rather than their marketing colleagues.

This clearly leads on to the question regarding at what point customer need should be determined, and by whom. In the end, patients are our customers and not prescribing physicians. It is evident that patients are emancipating themselves from physicians more and more – using publicly accessible sources to learn about their diseases and diagnoses. This trend is further supported by the increasing number of health systems that rely on patient contributions to pay for medicines, which also buys them into the decision-making process. So drugs are increasing purchased on perceived value rather than physician authority – at least in areas where taking the medication is not a question of life or death. Our determination of customer need also entails making a conscientious decision about which customers to listen to most. There are some customers that are always content with status quo and there are others who are always dissatisfied. The truth may lie somewhere in the middle but there is no clear way to estimate market forecast effectiveness. Or rather, there could be one but so far nobody has been motivated to collate all the data and to analyse them – to compare historic data with regards to market forecasts, with market fullfilment within predetermined therapeutic areas.

If we look at marketing-driven companies, the key to their success is good market research. Often market research looks back using the data from IMS in their various presentations. It also looks into opinions and there are different ways in which we can look into different data distortions. Focus interviews of individuals may develop a perspective into the future market if very creative individuals are cross-examined. However, focus groups are more frequently assembled and interviewed to explore a company’s concept. The group dynamic usually determines the outcome. I question whether this actually leads to a good forecast or whether it better reflects the relative strengths of the participants in the group discussion. Lastly many companies assemble advisory boards with what they like to call “key opinion leaders”. Some of these key opinion leaders may have been invited because they are very vocal, others because they could not be omitted for political reasons. I’m still looking forwards to prospective analysis of advisory board forecast outcomes versus reality. Other, less frequently used, methods include Delphi methods of forecasting and concept testing with patients or physicians.

If we looked for product development techniques that could make life easier for marketing, we should expect that the development cycles become shorter. Still, it takes many years for the development of a new chemical entity, some years for line extensions, and sometimes many more in indication broadening. I know of one pharmaceutical company executive who does not allow the marketing people to make mathematical predictions of sales until phase II has been completed. Even by that time, many of the product features have not been determined. I frequently see target product profiles for which it was clear that the truth would not be available before its time of launch – if not later. I think we should be more determined by customer need than by the big wide-eyes of marketing. The big wide-eyes of marketing may just reveal some sort of marketing myopia by looking at the big markets and over-looking markets in which significant improvements can still be made. Further, marketing often focuses on conventional opinion leaders that may not like changes to paradigms. Some companies have experienced big changes such as when histamine blockers took over from antacids or calcium antagonists from some of the older antihypertensive compounds, for example. It is not usually marketing that prevents this lack of foresight, but medicine. Medicine should, thus, be awarded its rightful place in product development and may perhaps dominate some aspects of marketing one day.

(C) 2008 – Alle Rechte vorbehalten

 

Forget proof of concept – Michael Herschel

Synopsis

The pros and cons of a broad phase II testing are provided. Broad phase II means several hundred patients, and includes the option of a phase II nested into the phase III trial. The question of whether it is possible to make an informed “go or no-go” decision is examined as is the impact on costs, safety of study participants.

In this, the second of “Herschel’s Heresies”, I would like to burn some of the textbook wisdom that: clinical phase II should to be done in small, highly selected numbers of patients (phase IIa), leading to phase (IIb and) III, the real pivotal trials.

The textbooks tell us that phase I in healthy volunteers is followed by small well-controlled clinical trials in a few hundred patients at most, which serve to show that the drug works – at least against placebo. Phase II, beyond that, is the phase where surrogate endpoints are to be used to allow for small sample size.

We shall therefore look at the assumptions underlying this approach and the actual conduct of it, being aware that some companies are already seeking a cautious distance from this dogma.

The assumptions are few
1. If one selects a highly homogeneous population, the variability is small in general and for the primary endpoint in particular.
2. Small focused trials allow us to make a clear decision whether to progress into phase III trials.
3. Selected populations give a high likelihood of few adverse events occurring thereby not negatively influencing the risk-benefit profile at an early stage of development.
4. Ethics Committees are more likely to accept small trials in the face of lack of knowledge of a drug rather than large ones.
5. As many of phase II compounds do not make it into phase III, large phase II trials are a waste of time and money.

Assumptions
Assumption 1)
I have selected an overview by Collins on diuretics in pregnancy. The sample sizes in the trials ranged from 78 to 2706 patients. There is no correlation between the sample size and the variability. Small samples may be more homogeneous, but they need not be. Similar conclusions can be drawn from a meta-analysis where intranasal steroids were compared to oral antihistaminics.
In addition, the reduction of variability greatly reduces information that may be relevant for phase III. For instance, the relationship between initial blood pressure and the effect of drugs becomes clearer if a wide range is included at the start.

Assumption 2)
The decision, after phase II, is whether to progress into phase III or stop clinical development altogether. For the latter decision there is a high post-decisional regret, thus the likelihood to “kill” a “good” drug must be very low. Whether this is achieved today cannot be said, however, there is anecdotal evidence that several companies have revitalised “dead” drugs and made them winners. Known examples are BI’s meloxicam and Bayer’s nifedipine. On the other hand, few compounds are killed after phase II altogether, except if they show no superiority over placebo in a trial where an active drug is also part of the treatment arm. About half of the drugs that are stopped are terminated after phase II because of lack of efficacy, the remainder showed safety problems or formulation difficulties.
The decision to go into phase III carries the risk of not having a drug but just a compound that showed a “proof of concept”. When taking a sample of compounds that died at the end of phase III or were not marketed, the following reasons were given:
– Lack of efficacy
– Safety problems
– Lack of superiority over gold standard

It is obvious that such information is desirable before beginning phase III. However, currently the phase II rarely allows a reliable decision regarding phase III.

Assumption 3)
The dogma of the selected population that does reduce the risk of side effects has never been questioned. From clinical testing of abacavir, for instance it can be said that both the frequency and body system profile was similar in phase II and III. However, larger samples increase the likelihood that the observed incidence is “real”.

Assumption 4)
Ethics Committees do not wish to give carte blanche. Therefore, less restricted populations would be more acceptable if the information on such adverse event profiles, be it directly or via Data Safety and Monitoring Boards, is fast and comprehensive. Funnelling such information via Internet or other means so that decisions by Ethics Committees are facilitated are a prerequisite.

Assumption 5)
The data on clinical trial cost is not too reliable. A small calculation may underscore this point: if a phase III program costs 50 million Euro, and if 50% of such decisions could be made by the end of phase II, then a company bringing four compounds into phase III each year could save 100 million Euro per year. On the other hand, of the 10 compounds it brings into phase II, additional costs could come up by enlarging phase II, i.e. on the basis of total cost per patient of 10,000 Euro and 300 additional patients, this would add 3 million Euro per compound, and thus allow a net gain of 100 minus 30, i.e. 70 million Euro.
Having discussed the cons of a broad phase II, let me briefly summarise the pros:

1. Recruitment of patients will be easier.If the criteria of eligibility are simplified and exclusion criteria are scrapped, the inclusion of patients will be faster. The likelihood finding patients will be higher, however, the problem of including women has to be solved by providing sufficient toxicology data.

2. The type of patients will be closer to realityThis issue follows from the first. While this may disappoint stock exchange analysts who like “great” phase II data, it helps to make a more realistic drug profile planning for the subsequent phases.

3. Safety problems may be known earlierSome of the safety problems may come up much earlier, such as features that may differentiate the new compound from the marketed competitors.

A broad phase II may not be a panacea for all clinical development. When a drug is developed for a disease where no drug is available yet, a small phase II versus placebo may be all that is needed. But in all other cases, where a dose-response-relationship needs be established early and reliably, the current policy tends to lead to the usual phase IIb before phase III is started, and, therefore, to a loss of time and money. It seems that a compromise is the phase II that leads almost automatically into phase III which is sometimes is called “nested”.

But why, then, do we still teach newcomers that “phase II is done in small samples of patients” ?.

(C) 2008 – Alle Rechte vorbehalten

World without Ethic Committees – Michael Herschel

In history, heretics needed much courage and frequently ended up burnt for their efforts. Nevertheless, they often set the scene, stimulated others, and, ironically, may have been celebrated – had they only lived some decades later. The author of these heresies is somewhat courageous, but prefers other forms of death. He would also prefer to be celebrated alive!

Several decades ago, there was a world without Ethics Committees (EC), or, as they are called in the United States, Institutional Review Boards (IRB’s). Even for years after the Declaration of Nuremberg, condemning the abuse of prisoners for pseudo-medical experimentation, EC’s were the exception rather than the rule.

Let us therefore remember their major remit: to protect trial subjects. For this purpose, a number of critical questions need be answered:

– Is the population able to voluntarily give informed consent?
– Does the expected benefit exceed the risk or at least not be less than the risk?
– Is the information to the trial subject true, clear, and can it be understood?
– Is there any obvious or clandestine coercion on trial subjects to participate?

Looking back over the years, there is little hint that EC’s and IRB’s failed to protect the patients effectively. Where they failed, it was rarely before the trial, but during the trial, as they did not monitor its progress. In some major trials, Data Safety Monitoring Boards (DSMB) have taken over some of these genuinely EC tasks. But as said, the overall record is good, irrespective of whether, or not, their composition was exactly in accordance with the ICH-GCP recommendations. It should be noted, however, that EC’s usually are not controlled or audited by anybody. Therefore, a slight risk remains.

For various reasons, EC’s have taken on other tasks only remotely related to the protection of trial subjects. They have embarked on commenting trial design beyond its acceptability from a subject protection view. They have discussed investigator payments. They have questioned the statistics of a trial. They have, at times, found that any sort of payment to patients is unacceptable.

One of the frequently debated questions is how many EC’s need to have a look at the trial. In, my home country of Germany, the EC of the Principal Investigator is legally, the only relevant one. However, universities also have their own EC’s. Additionally, the regional Physicians Associations also maintain their right to vote independently. Admittedly, among the latter, more are now accepting the opinions of others without going into details. When asked why they do not acknowledge the wisdom of the „primary“ EC, the following reasons are given:

– we have a law or regulation whereby our members must ask us (this law was made by them and could easily be cancelled)
– we do not trust in the opinion of the other EC (which usually as nothing to do with actual poor performance of the other EC but with a feeling of being superior)

The added value of the second and third and umpteenth EC has never been proven. Our own records tell me that only very minor improvements regarding patient protection result from multiple opinions. Nevertheless, the four-eyes principle used in accounting could be extended beyond the one committee to a second (but not any additional ones) if more investigations would support this procedure. I strongly believe that the loss of time currently resulting from infrequently meeting EC’s and their multiplicity is not warranted.

Little quantitative research is available. Therefore, I suggest a research agenda on the value of EC’s to support our assumptions with hard data. But beyond that, and in order to enhance the trust in this institution, I suggest to have them supervised by an accreditation body that is controlled by a democratically elected body, for instance by a ministry or parliamentary subcommittee. This would result in a single, more professional review and probably a shorter review time.

Let us for a moment come back to the title of this article. Although we know little about what may have happened, I would not feel comfortable in a world without Ethics Committees. While most, and especially the global pharmaceutical players have little or nothing to be criticised for by an EC in their trials, there are some „black sheep“. Additionally, there are the many investigations, not sponsored by a pharmaceutical company, frequently without any adequate patient information which are never reviewed by an EC.

It is for these reasons that I suggest to re-direct the focus to the patient. Instead of the inflated „Ethics Committee“ with many questions irrelevant to the physicians dictum „nil nocere“ (do no harm), I would like to suggest Patient Protection Committees (PPC) which are properly accredited, controlled by the accrediting body, and accountable. Furthermore, for a single trial, a single review should suffice.

(C) 2008 – Alle Rechte vorbehalten

Does Source Data Verification (SDV) need a revolution? – Michael Herschel

Synopsis
Source Data Verification (SDV) demands a large part of the work of clinical monitors. An inherent philosophy that has indoctrinated the belief that clinical data should be transcribed onto the CRF from source documentation remains normal practice. Ideas are changing and it is now proposed that all trial data are entered in the CRF, which is the source document during the course of the trial. Only pre-screening data that testify the patient’s existence, medical history and concomitant medication, should be recorded elsewhere. It may be necessary to put aside inherent philosophies and comfortable practices in order to become more efficient in our development of monitoring strategies and more effective in our use of modern technologies.

Does Source Data Verification need a revolution?

Philosophy and Status quo
For years, clinical trial philosophy has indoctrinated a popular belief that most clinical trial data reside in the patient’s chart, which is kept in the physician’s office. Some “non-standard” data are recorded directly onto trial-specific forms, but the majority of “standard” data are transcribed from the physician’s file (e.g. laboratory test results, medical history and adverse event data) into trial notes.

Even today this inherent belief leads to situations whereby investigators record everything on the Patient Chart first and then transcribe it elsewhere. This process introduces countless transcription errors, which lead to queries and audit findings. Conversely, some investigators use the Case Record Form (CRF) to record their findings and then transcribe the data onto the Patient Chart because this is more convenient for them. In all fairness, even the International Conference on Harmonisation (ICH) guidelines are unclear about the process of source data verification (SDV) and the frequency of its conduct. The guidelines stipulate that the goal of SDV is to ensure that the data recorded in the CRF are accurate. One way to check this is to compare the CRF with the “source data” recorded on the patient’s chart and in the physician’s notes.

Arguments againt SDV
Source data verification can be considered an exceptionally expensive way of ensuring that two sets of data are congruent. This does not mean that both sets of data are a true representation of the findings; rather that they are identical. From this perspective, a more sober look at SDV is possible. Most trialists concede that verification of the patient’s identity, medical history, and concomitant medication is an essential prerequisite to patient enrolment. Documentation of all other information could be recorded in the CRF. Thus, the CRF should be the source document on which all patient data are entered. Any additional information not required by the trial protocol, could be entered on the Patient Chart provided that a note is placed on the chart linking the two sets of databases to each other.

It is my opinion that technology has already enabled this process to develop a stage further. Electronic data capture (EDC) makes it possible to type data directly onto a CRF without the need for paper. The data then flow directly into a database. Some regulatory agencies have formed draft guidelines, which stipulate conditions under which such systems and processes can be used. Nevertheless, most companies are hesitant to withdraw the use of pen and paper entirely.

If SDV was a simple and straightforward procedure no one would be trying to “simplify” the process with other technologies. However, the philosophy behind SDV is questionable – which elevates its already high cost. A key reason for periodic monitoring visits is to verify the CRF with the source data. The cost for a periodic monitoring visit, including all expenses, can be between $500 – 1000. Most companies only have the resource to conduct one monitoring visit per day (although there is still some room for improving productivity). In addition to inflated monitoring costs for sponsors, data transcription necessitates additional time and effort on the part of the physician. In turn, this has an effect on investigator remuneration, as the trial demands more of his or her time and resources.

Regulatory Opinions
A brief survey conducted by telephone to sample regulatory opinion has shown that regulatory personnel do not wish to be seen to be being too “liberal”. Some of the agency representatives maintained that SDV is “necessary” but were not prepared to endorse the 100% SDV initiatives that some companies are aiming for. Others felt that it was up to the industry to come up with proposals that would liberalise the process whilst maintaining the integrity of the data and adhering to data protection laws.

Personal Experience
Personal Experience
In an attempt to quantify the “value added” by SDV, GlaxoWellcome screened 20 of its internal site audits to determine the number of audit findings that related to SDV. In addition, monitors at GlaxoWellcome completed an internal questionnaire about the effectiveness of periodic monitoring visits in uncovering discrepancies between the source data and the CRF.

The results of this survey showed that although SDV improves the accuracy of data it adds little value to the trial and, at best, may be considered costly. On the other hand, it could be concluded that a significant reduction in SDV would lead investigators to believe that a reduction in transcription accuracy was acceptable. This clearly is not the case and here statistical quality control could be of benefit. A quality control strategy that introduces a “sliding scale” i.e. number of spot checks increases in proportion to the number of discrepancies found, would be an efficient and effective way of conducting site audits and would compensate for the reduction in monitoring visits.

Conclusion
The conduct of SDV is in need of a revolution. Paperless offices and electronic digital data exchanges are becoming more common. Nethertheless, most of us are still collecting the majority of our clinical trial data on NCR paper and comparing the data to entries in the patient files from which they have been transcribed. In the face of escalating drug costs and static time-to-market periods, we must work together as an industry to revolutionise data capture. It may be necessary to put aside inherent philosophies and comfortable practices in order to become more efficient in our strategy development and more effective in our use of modern technologies. Radical changes to the way in which we conduct SDV would be a significant step in the right direction.

(C) 2008 – Alle Rechte vorbehalten