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Balancing early market access to new drugs with the need for benefit/risk data: a mounting dilemmaHans-Georg Eichler, Francesco Pignatti, Bruno Flamion, Hubert Leufkens and Alasdair Breckenridge

Abstract | Drug regulatory agencies are increasingly pressed by the challenge of finding the appropriate balance between the need for rapid access to new drugs and the need to ensure comprehensive data on their benefits and risks. This dilemma is not new, but has been made more prominent by recent high-profile drug withdrawals and conflicting demands, including the need to improve the efficiency of drug development on one hand, and the need to avoid exposing patients to unnecessary risks or possibly ineffective treatments on the other. Here, we summarize the current demands by stakeholders and the scientific and regulatory issues at stake, describe existing and emerging regulatory approaches, and speculate on future directions, such as evolution of the current regulatory model from a one-off marketing authorization to a life-cycle approach.

A mounting challenge faced by drug regulatory agencies today is the act of balancing the need for rapid market access to new drugs with the need for comprehen-sive data on the benefits and risks of the new drugs. This dilemma has been exacerbated by recent experiences, including high-profile drug withdrawals from the market (for example, cerivastatin (Baycol) and rofecoxib (Vioxx)), and post-marketing concerns over safety (for example, tegaserod (Zelnorm) and rosiglitazone (Avandia)). These are in addition to concerns over lack of efficacy (for example, gefitinib (Iressa)), or integrity of clinical trial data (for example, telithro mycin (Ketek)1).

The regulator’s dilemma reflects the various needs and interests of stakeholders, all of which appear legitimate when con-sidered in isolation, but which are difficult to reconcile with each other (FIG. 1). On one side, there is mounting criticism of regulatory agencies for allowing drugs on the market too early, with members of the scientific community and consumer advo-cacy groups (for example, Public Citizen; see Further information) calling for more comprehensive pre-marketing safety data2,3 and for more thorough assessment pro-cedures4. In some health-care environments, this is echoed, albeit for different reasons, by health economists and third-party payers (such as insurance companies and national

health services). These stakeholders would urge regulators to require more and also different, pre-marketing data, including information on relative efficacy, and increased emphasis on external clinical trial validity; that is, information on drug effec-tiveness5,6. Such demands, although justified in many instances, would translate into a requirement for expanded pre-authorization development programmes and longer time to market approval.

At the same time, there is an increas-ing awareness of the humanitarian cost of delaying or preventing access to potentially life-saving drugs. This is illustrated, for example, by the activities of an increasing number of patients’ organizations, by a report by the World Health Organization7 and by many sections of the pharmaceutical industry, which denounce what is perceived as an increasingly risk-averse regulatory culture. The pharmaceutical industry points out that further raising the bar for regulatory approval will stifle innovation and create disincentives for investment in drug research. According to these stakeholders, regulators should use more flexibility to facilitate innovation by lowering the barriers of market entry.

In this article, we provide a regulatory perspective on the challenge of balancing early market access with uncertainty about benefit/risk profiles of new drugs. Here, the

term ‘access’ is intended to denote market access (that is, the granting of a marketing authorization or licensing) of a drug, rather than ‘treatment access’ by individual patients. For many drugs, treatment access also involves a subsequent decision on reimbursement of an authorized drug by third-party payers such as Medicare in the United States or national health services in the European Union.

Scientific and regulatory issuesTrading uncertainty about benefit/risk balance for earlier market access. All regula-tory decisions, no matter the field, are taken under conditions of uncertainty. For the assessment of the benefit/risk balance, the overall level of uncertainty is related to all the constituent uncertainties of safety and efficacy parameters. Even when efficacy is assessed under controlled experimental conditions, uncertainty arises from multiple sources, such as gross experimental error, systematic error and bias, and random errors. Random errors, which are character-ized as the well-known type I and type II errors of clinical trials (that is, the risk of reaching a false-positive or false-negative conclusion, respectively), can be limited, but not eliminated. Surprisingly, gross experimental error (for example, use of non-validated surrogate end points or questionnaires) and bias (for example, asymmetric schedules of assessment or use of historical controls), which could gener-ally be minimized through appropriate design of the studies, are still commonly encountered by drug regulators and are much more challenging to account for at the time of review8.

Uncertainty about safety may be even greater, as most studies for regulatory approval are powered to demonstrate effi-cacy, not safety. So, each regulatory decision entails a level of acceptable uncertainty about the benefit/risk assessment, below which regulators may be prepared to take a positive decision on a new drug licensing application, and above which they would be negative. The problem is that the threshold of acceptable uncertainty cannot usually be described by a single metric; neverthe-less, it is implicitly factored into regulatory decisions.

Analysis of past regulatory decisions supports the notion that the level of accept-able uncertainty is not constant across all therapeutic indications. Regulators are generally willing to accept a higher level of uncertainty around the benefit/risk assess-ment for life-threatening or otherwise severe

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IndustryRequire favourable conditions for

innovation

Shorter timelinesHigher level of uncertainty

Unmet medical needFor example, epidemiology of obesity,

diabetes

Patient groupsDemand early access to potentially life-

saving drugs (for example, Abigail Alliance)

Payers/prescribers/HTA organizationsRequest comparative efficacy/effectiveness data

More studies/patientsDelayed market access

Excess medicalizationFor example, obesity, metabolic syndrome, mood disorders

Media/scientific communityDemand stricter safety assessment after series of market withdrawals

Time to marketing authorization

conditions for which there is a high unmet medical need, as opposed to less severe con-ditions. Thus, the approval of several oncology drugs has been based on relatively small numbers of patients enrolled in clinical trials compared with non-life-threatening indica-tions, or based on single-arm trials and/or surrogate endpoint information9. Single-arm trials are generally considered to yield less robust information than randomized controlled trials (RCTs), and there is often uncertainty over whether the surrogate end point will ultimately be validated. Such trials may not be acceptable for drugs intended for treatment of less debilitating conditions.

Pitfalls and unintended consequences of earlier market access. Regulators acknowl-edge the need to facilitate innovation and the fact that lack of efficacious therapies is a public health issue10. In addition, there is the legitimate concern of seriously ill patients that “years of delay… means a lot of people for whom doors may not open until it is time for them to shut”11. Nonetheless, the readiness of regulators to bring forward the timing of marketing authorization is often restricted by a number of considerations.

First, enthusiasm is dampened by past experiences in which, even with standard timelines for market access, the benefit/risk assessment worsened with increasing post-marketing experience, necessitating drug withdrawals, restrictions or warnings. If marketing approval was moved forward — for example, to around the end of Phase II clinical trials, as was proposed by at least one commentator12 — such cases would be expected to multiply, as the number of candidate drugs failing in Phase III trials continues to be approximately 45%13. Moving the approval systematically to Phase II would not only shrink the safety database but would also be a fundamental change in the efficacy standard.

An example of this scenario is provided by the regulatory history of gefitinib (Iressa; AstraZeneca) in the United States. This drug was approved for non-small-cell lung cancer, a condition of high unmet need, by the US Food and Drug Administration (FDA) via an early access procedure and on the basis of two single-arm trials with objective response rate as the primary end point. The response rates observed in these studies were deemed to indicate sufficient pharmacological activity to warrant accelerated approval, provided that further studies would conclusively demonstrate patient benefit. However, subsequent results from a randomized, double-blind study demonstrated no effect

on survival for gefitinib in comparison with placebo. In response to these disappointing results, the FDA restricted the label for gefitinib from “monotherapy for the treat-ment of…” to “monotherapy for the con-tinued treatment of….” non-small-cell lung cancer. In an accompanying alert, the FDA informed prescribers that: “the medicine should be used only in cancer patients who have already taken the medicine and whose doctor believes it is helping them. New patients should not be given Iressa….” This unique regulatory action may have been the best possible course to take under the circumstances. However, this case illustrates how an increasing number of such drug withdrawals would not only undermine public trust in the regulatory system but also present a conundrum to patients and caregivers.

A second reason for the reluctance by regulators to grant earlier approval is, again, based on past experience. That is, earlier approval is usually granted on the condi-tion that certain pre-agreed post-marketing studies will be undertaken by the marketing authorization holder (MAH) to enable more refined benefit/risk reassessment. However, such study results have sometimes been difficult to obtain. In a survey of the status of open commitments for post-marketing studies requested by the FDA, Avorn14 reported that more than half of the studies were not yet started, behind schedule or terminated before completion. Although it has been clarified by the FDA that this is not synonymous in all cases with failure to fulfil commitments15, this paper has highlighted a critical issue: what is the most appropriate

regulatory action to take in the event that promised studies are not performed or anticipated data do not become available? Taking no action and leaving the marketing authorization unchanged would undermine the system, whereas revocation or restriction of the licence, simply based on a lack of new data, will be difficult to argue before patients and health-care providers, particularly in the case of a potentially life-saving drug.

Third, there is a concern that some post-marketing data may never become available, irrespective of the motivation of the MAH to conduct studies16. This is because early approval may reduce the willingness of patients to enrol in RCTs if they could have access to novel drugs by way of standard care. So, early approval may have the unintended consequence of closing a window of oppor-tunity for performing the very studies that regulators would require to follow-up their positive licensing decision.

Acceptability of trade-offs for earlier market access. In recent regulatory history, early market access has usually been based on one or more of the following strategies: biomark-ers and/or surrogate end points; results from interim analyses; and a reduced-size safety database.

The first strategy — use of biomarkers (quantitative measures of biological effects that provide informative links between mechanism of action and clinical efficacy) or surrogate end points for efficacy (quan-titative measures that can predict efficacy) — can drive rapid clinical development and early access. For example, regulatory adop-tion of CD4 cell counts and, subsequently,

Figure 1 | The regulator’s dilemma. Regulators are confronted with a growing number of external needs, stakeholders, and their interests and concerns. All of these factors influence, or seek to influence, the timing of marketing authorization, which determines the time at which patients gain access to new drugs. The conundrum results from the fact that some of these external forces, although often legitimate in their own right, are pointed in different directions and become irreconcilable. HTA, health technology assessment.

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measures of viral load as surrogate markers for the efficacy of anti-HIV drugs allowed the rapid approval of life-saving antiviral drugs, with time from first-in-human use to market as short as 3.5 years17. This success stimulated growing enthusiasm for bio-markers in many therapeutic fields. Both the FDA’s Critical Path Initiative18 and the EU’s Innovative Medicines Initiative19 list the development of new biomarkers and surrogate end points of efficacy as key goals.

However, the regulatory history of the use of surrogate markers for drug licensing is a troubled one, and in at least one instance (the use of electrocardiogram signals to predict mortality reduction by some anti-arrhythmic agents) gave rise to treatments that were later shown to reduce patient survival20. Surrogate end points have recently been brought back into sharp focus by the controversy over the safety of the diabetes drug rosiglitazone. Results based on meta-analysis of clinical outcomes purported to show that rosigli-tazone may increase the risk of myocardial infarction and possibly death from cardio-vascular causes — some of the very risks that diabetes management is supposed to reduce3. like all new diabetes drugs licensed to date, rosiglitazone was approved on the basis of its demonstrated ability to lower HbA1c, a measure of glycaemic control. While it should be acknowledged that debate on the benefit/risk profile of rosiglitazone is still evolving, this meta-analysis has already challenged the biologically plausible paradigm that improved glycaemic control will necessarily translate into favourable effects on patient-relevant outcomes21. Along similar lines are the implications of the recent report of a Phase III study that addition of torcetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, to atorvastatin treatment increased the risk of cardio vascular events and death from any cause. This occurred even though the treatment seemed to produce the anticipated favourable effects on lipid profile, highlighting the notion that even well-estab-lished surrogate end points might not predict the clinical outcome because the surrogate marker does not capture off-target effects22.

The implications of such experiences for regulatory policy are considerable. If regula-tors were to insist, for instance, on clinical outcome studies for all novel diabetes agents, as some commentators have suggested23, this would add several years to the drug development process. The consequences of this could be a significant raising of the entry barrier for the current diabetes pipeline of more than 70 novel agents24. It remains to be speculated to what extent such a regulatory

policy would lead pharmaceutical compa-nies to pull back from developing drugs for a condition that is becoming an ever increasing public health burden.

The second strategy of early licensing that is based on the results from interim analyses of a pivotal clinical trial seems an attractive option, particularly in cases in which the full trial results would not become available for a long period. Interim analyses may lead to the early observation of unexpectedly large treatment effects and, when properly planned and conducted, are considered to be the only coherent method to guard against severe underestimation of the treatment effect at the planning stage. In the past, interim analyses that were based on sound methodology and robust statistical evidence have been accepted for early approval. For instance, the FDA granted accelerated approval to oxaliplatin (Eloxatin; Sanofi–Aventis) for metastatic colorectal cancer based on a surrogate end point at the interim analysis, followed by full approval based on the final analysis including data on clinical benefit25. More recent exam-ples in the European Union are trastuzumab (Herceptin; Roche/Genentech) for adjuvant treatment of patients with early breast cancer (an extension of the indication) and lapatinib (Tyverb; GlaxoSmithKline) for advanced or metastatic breast cancer. In the latter case, the result of a pre-planned interim analysis of the Phase III trial based on median time to progression allowed the European Medicines Agency’s (EMEA’s) Committee for Medicinal Products for Human Use (CHMP) to recom-mend a conditional marketing authorization of lapatinib26. It may be estimated that this approach has brought forward patient access to this drug by 1 year, if not more.

These examples notwithstanding, early approvals based on interim analyses present regulators with additional uncertainty. Interim analyses only look at selected end points in a selected trial population. late events may be under-represented and long-term effects will generally be unknown. By contrast, final analyses come with a comprehensive and mature data package in which the primary end point and all second-ary end points can be examined together. Thus, special care is needed when selecting the timing and alpha spending of interim analyses. A further regulatory concern is that interim analyses have an inherent risk of damaging the integrity of the trial and introducing bias. Therefore, the informa-tion flow should be rigorously controlled and adequate firewalls between the data monitoring committee, the sponsor and the participating investigators are required.

With regard to the third strategy of a reduced-size safety database, although current expectations around the ability of biomarkers and surrogate end points to speed up the time to market are usually focused on earlier demonstration of efficacy, toxicity is a leading cause of attrition during the development process and of restrictive regulatory action post-approval. So, even the best available markers for efficacy would not necessarily reduce the time to marketing approval as safety concerns (the other side of benefit/risk assessment) increasingly become the rate-limiting step. When con-sidering the issue of how much safety data is enough for regulatory approval, it is useful to distinguish between predictable and unpre-dictable adverse drug reactions (ADRs). Signals that may predict clinical safety issues could arise from: the chemical structure or physicochemical properties of the active substance (for example, many cationic amphiphilic drugs cause phospholipidosis); its primary pharmacology (for example, the risk of insulins to produce hypoglycaemic attacks); well-understood secondary phar-macology (for example, the gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs)); metabolism (for example, potential for drug–drug interactions or for-mation of reactive metabolites); and results from the preclinical and clinical develop-ment process or from clinical experience with drugs in the same or similar classes27.

Whatever the source of a safety signal, it is difficult to see how regulators could not insist on a thorough understanding of its clinical implication, even at the cost of delayed approval. That regulatory agencies cannot escape such a reaction has become evident after the severe criticism they received for not giving due consideration to preliminary safety signals emerging from the basic pharmacology and from earlier clinical trial data of the cyclooxygenase 2 (COX2) inhibitor rofecoxib (Vioxx; Merck)28. The consequences from the highly publicized rofecoxib debate offer a useful example of how a safety signal may come to affect the regulatory environment for a large and hetero geneous class of drugs. Several lines of evidence have since suggested an increased cardiovascular risk from COX2-selective and non-selective NSAIDs. Current data also seem to indicate that there may be differ-ences in the cardiovascular risk of individual COX inhibitors; the possible mechanism of these effects is not fully understood29. While there is no recent experience of marketing applications for new compounds in this class, regulators may be obliged to request

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Background incidence

Frequency of additional drug-related events

1×107

1×106

1×105

1×104

2/1,000 4/1,000 6/1,000 8/1,000 1/1001×103

1/100 1/500 1/1,000 1/5,000

a full set of clinical data addressing cardio-vascular risks in case of future applications, except perhaps for short-term pain-relief indications. These requirements will prob-ably raise substantially the entry bar for any future NSAID in a major indication.

On the other hand, proponents of more stringent regulatory safety requirements should remember that not all types of drug toxicity are predictable, as highlighted by idiosyncratic ADRs27,30. Basic rules of statis-tics explain why for these unexpected ADRs even the most stringent regulatory standards and even a delay of marketing approval by many years would not guarantee a positive benefit/risk balance at a given time after marketing authorization. Inspection of the relationship, illustrated in FIG. 2, between the incidence of a given ADR, the spontan-eous background incidence of this particular event and the minimum number of patients required in clinical trials to detect the ADR shows that demonstrating an absence of risk requires unrealistically large numbers of patients under observation. For example, a RCT that includes 7,000 patients in two treatment groups (which would make it a very large programme by current standards) will only have a <50% power to detect an increase of 1 in 500 incidence of an ADR that has a background incidence of 1 in 1,000 patients (one-sided test, alpha = 5%). Yet if that ADR was lethal, it could be argued that even a drug-induced rate of 1 in 5,000 (one-fifth of the background inci-dence) might tip the benefit/risk balance towards negative, and the drug should not be approved (after all, if the drug came to market and was used by 1 million people, that ADR would cost 200 lives). The same trial with 7,000 patients would have virtually no power to detect such an increase. To detect this ADR with 90% power would require a RCT with around one million patients, a require-ment that is clearly not compatible with the realities of drug development31,32.

This example and the data shown in FIG. 2 lead to the following conclusions. First, rare drug reactions will continue to be identified only after wider use in the market. Second, a small drug-induced increase in the frequency of an event, particularly of a very common event (for example, the purported increase in myocardial infarctions due to rosiglitazone) will continue to be difficult to detect before marketing, even in the course of the most comprehensive development programme. Third, a meaningful improve-ment in the power of pre-marketing studies to detect rare, unexpected ADRs would require the safety database to be expanded

not ‘somewhat’, but by at least an order of magnitude (FIG. 2). last, and most impor-tantly, post-marketing drug withdrawals due to rare but severe ADRs are not likely to become a thing of the past, do not necessarily indicate failure of the regulatory processes and have to be accepted with any model of drug approval — early or late. It has been pointed out that “the only alternative is to not approve anything”33.

Another recent development that will probably affect the dilemma of early versus late approval is the emerging requirement for relative efficacy information at the time of approval5,6. To date, demonstration of an effect in comparison with placebo in a RCT is usually considered sufficient for estab-lishment of efficacy and comparative infor-mation — that is, head-to-head comparison with best available treatments — is not a regulatory requirement for the majority of treatment indications. Only 48% of new active substances authorized between 1999 and 2005 through the European centralized procedure have been studied in an active-controlled trial6. Several commentators and reimbursement organizations have pointed

out that the lack of comparative data greatly hampers assessment of the therapeutic value of medicines by prescribers, formu-lary committees and other health-care decision-makers. Although the usefulness of comparative information is undisputed, it must be remembered that a push for more active-controlled trials will, in most instances, require larger and/or longer trials to demonstrate either super iority (because efficacy differences between treatment groups are expected to be smaller than in a placebo-controlled trial) or non-inferiority against best-available treatment. This would effectively delay the time of approval.

An even more far-reaching line of argument advocates that, for ethical reasons, new drugs should be required to have some added value (greater efficacy or less toxicity) relative to current treatments28,34. If this paradigm was indeed adopted by regula-tors and demonstration of non-inferiority would no longer suffice to obtain marketing approval, the number of new drugs coming to market would be expected to decrease further. While this consequence might not necessarily be detrimental to public health,

Figure 2 | The challenges of identifying rare adverse drug reactions in clinical trials. The ability of clinical trials to spot rare adverse drug reactions (ADRs) depends on statistical assumptions; trial size (the number of patients enrolled in the study); the frequency with which the drug induces the ADR (for example, how many more myocardial infarctions would be caused when 1,000 patients take the drug); and the background incidence of that event (for example, incidence of myocardial infarction in the target population). The figure illustrates that a study of more than 160,000 patients would be required to detect a 1 in 1,000 incidence of drug-induced myocardial infarction in middle-aged men (large round symbol in graph; one-sided test, alpha = 5%, power = 80%), given a background incidence rate in the UK for men aged between 30 and 69 of about 6 per 1,000 (ReF. 52). A 1 in 1,000 rate of drug-induced myocardial infarction may be considered unacceptably high for a drug intended for a non-life-threatening disease, and — if known — would probably turn the benefit/risk assessment negative. However, conducting a study of that size is not realistic in the context of most pre-marketing development programmes. Requesting such trials as a basis for licensing would hamper innovation and severely delay access to new drugs.

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Know

ledg

e

Time

Severity of condition/unmet medical need

a c

b

Knowledge surface

at least in the eyes of the paradigm’s proponents, it would nevertheless delay the availa bility of added-value drugs for the reasons described above.

Regulatory tools to tackle the dilemmaConditional/accelerated approval. legal provisions are in place in various jurisdic-tions including the European Union (the EMEA’s conditional marketing authori-zation or conditional approval35) and the US (the FDA’s accelerated approval36) to enable early access by patients to drugs that fill an unmet medical need. It should be noted that conditional approval and accelerated approval are distinct from compassionate use programmes that are available in some countries. Although these programmes can be institutionalized, such as the Autorisation Temporaire d’Utilisation scheme in France, and may be very efficient in allowing early access to a small number of select patients, they do not involve granting of a licence, and are not discussed here.

In most cases, granting conditional approval or accelerated approval requires regulators to exercise their widest possible flexibility, which is tantamount to accepting a higher level of uncertainty about safety and/or efficacy, as conceptualized in BOX 1. Conditional approval is reserved for life-threatening or severely debilitating diseases in which there is an unmet medical need and in which information available at the time of approval suggests that the net benefit is positive (see BOX 2 for an example). The legal framework of early access both in the European Union and in the United States dictates that this increased level of acceptable uncertainty must be temporary. That is, additional data is requested that must be provided by the company in due time in order to reduce the uncertainty around the marketing authorization decision to a generally acceptable level.

However, the EMEA’s conditional approval is a new regulatory tool that needs further testing and probably refinement before its full potential can be ascertained. Regulatory decision-makers need to be assured that the outstanding informa-tion inherent to conditional approval will indeed become available; that is, that studies required will be initiated by the MAH and will be feasible and ultimately interpretable. lack of anticipated follow-up data would put regulators into a position even more difficult than the gefitinib case described above, as the uncertainties would persist potentially indefinitely. EU legisla-tion has introduced the possibility of using

financial penalties to deal with cases of lack of diligence in conducting the post-approval studies.

Staggered approval. An approach with some similarities to iterative benefit/risk assessment by regulators is dubbed ‘staggered’ approval by varying the approved indication. Staggered approval may be a useful route to enable early drug access, based on limited clinical experience, to patients with a high unmet medical need. It involves granting a licence for a narrowly defined subset of a given disease population

by way of strict diagnosis criteria, limiting prescribing to centres of excellence, or similar measures. An expanding need for such early but limited authorization is reflected by recent legislative changes in the United States now granting the FDA the authority to restrict a drug’s distribution to physicians in particular specialties or to particular settings in which the benefit/risk assessment justifies close control of its use31. As more data are provided, such restrictions might be progressively relaxed, widening the access to broader patient subpopulations.

Box 1 | Evolution of the regulatory threshold

Knowledge about the benefits and risks of new drugs grows over time. Along this continuum of information gain, the position of the regulatory approval threshold — how much information is enough to allow a drug on the market? — is not a given. Experience indicates that the threshold is to some extent dependent on the degree of unmet medical need in the target indication. For example, a high unmet need such as a life-threatening disease for which there is no effective treatment would be associated with a lower need for information. In the figure, this is depicted by the solid line running diagonally across the ‘knowledge surface’. The arrows (a, b, c) symbolize case studies in the current debate on — and regulatory practice of — balancing early access with the need for sufficient information on benefit/risk assessment. The dotted line denotes a widening gap in regulatory requirements between drugs for life-threatening versus non-life-threatening diseases. Such a scenario may possibly develop in the future as a result of external pressures on the regulatory environment.

In conditions of exceptionally high unmet medical need (a), regulators may temporarily lower the requirement for comprehensive benefit/risk data, to enable rapid access to promising drugs (the threshold moves temporarily to the left). Legislation was introduced in the European Union (EU) — conditional marketing authorization — and in the United States — accelerated approval — to specifically address such cases. An example of conditional marketing authorization is sunitinib (BOX 2).

For some drug classes, an emerging safety issue may seem to necessitate pre-marketing clinical studies of such size or duration as to render the development of new drugs unrealistic (b; the threshold would move to the far right). Regulators and sponsors will need to identify ways to continue allowing reasonably early market access, while ensuring that safety data will be provided in due course. This need is addressed by EU legislation introducing risk-management systems. Examples for (b) include non-steroidal anti-inflammatory drugs and some anti-diabetes drugs, which are described in the main text.

Enabling early access for patients with a high unmet need may also be achieved by focusing initial clinical development on, and granting approval for, narrowly defined subgroups within a given disease population. As more information on benefit/risk is accumulating, the licensed indication is widened (c; the threshold moves progressively forward along the unmet medical need axis). Examples of (c) include some HIV and cancer drugs, which are described in the main text and in FIG. 3.

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This approach has been successfully applied to a number of HIV drugs, which were initially licensed only for treatment of patients with advanced immunodeficiency or experiencing virological failure. After provision of additional clinical-trial data, the indication was widened to include treatment-naive patients. In a different form, staggered approval has been almost standard for anticancer drugs, which are often licensed for one limited indication at first (usually the most promising pathology in the eyes of the sponsor), but receive subse-quent additional indications. An illustrative example of staggered approval along this path is imatinib (Glivec/Gleevec; Novartis). Imatinib was first approved in the European Union in November 2001 for very narrowly defined conditions, but by the end of 2007 it had been granted an array of different indications in several jurisdictions, making it one of the best-selling drugs worldwide (FIG. 3). The two examples in FIG. 3 not only show how regulatory access to one product may be staggered for different disease populations, but also illustrate that the regulatory route towards blockbuster status may become ever more complex.

Risk-management system and life-cycle management. There is broad agreement among regulators and within the scien-tific community that the point of approval should not be the ‘last call’ for major regulatory action but that benefit/risk assessment is an ongoing activity, ideally spanning the full life cycle of a drug37. To achieve this goal, and to overcome the problem of missing post-marketing data described above, various jurisdictions have enacted, or are considering, legislations to establish post-marketing risk-management systems (RMSs).

A useful example is recent European legislation38 that provides for mandatory RMS, defined as: “a set of pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to medicinal products, includ-ing the assessment of the effectiveness of those interventions”. Sponsors are requested to submit a detailed risk-management plan (RMP) as part of the marketing authoriza-tion application dossier (or on a number of other occasions specified in the legislation). The RMP is discussed and agreed upon at the time of licensing. It should describe the post-marketing studies that the spon-sor commits to conduct. These may cover a range of designs, including intensive monitoring schemes, prescription event

monitoring, patient registries, various other types of observational studies, and clinical trials, up to large simple trials39. The RMP is not limited, though, to the identification and characterization of safety issues but includes measures to minimize or prevent known or suspected safety risks. It may include the conduct of additional preclinical studies to understand the mechanism of action and the impact of some potential or recognized adverse events.

Establishing a comprehensive RMS stems from the realization that pharmacovigilance systems that have been in place for some time need to be augmented. Current pharmaco vigilance is often based on spon-taneous reporting of adverse reactions by health-care professionals (hence, sometimes called passive reporting systems). While this has proved useful — over the past few decades several important drug safety issues have been identified through the existing pharmacovigilance tools — the lack of a denominator and controls makes it difficult to distinguish signals from background noise. Hence, spontaneous reporting alone is not sufficient to provide adequate safeguards to allow early drug approval.

limited experience available to date does not allow us to judge the overall impact of a comprehensive RMS, but it is hoped that this proactive approach will inform more “learning–confirming” cycles40 throughout the drug’s life cycle and into the post-marketing phase. This in turn is expected to allow regulators who are faced with an increasingly risk-averse environment to continue granting early (limited) approval by conducting repetitive benefit/risk assessments.

Harnessing the potential of health-care data-bases to assess post-marketing benefits and risks. At the time of approving new drugs, regulators rely mostly on RCTs submitted by sponsors. Although the RCT is rightfully the gold standard for determining efficacy, it suffers from a number of well-described weaknesses. These include cost and time requirements, numbers of patients that are usually too small to detect rare ADRs, and assessment of efficacy rather than real-life effectiveness. Some of these inher-ent shortcomings could be addressed by pharmaco epidemiological studies; that is, observational studies of drug effects based on electronic health-care data, such as pre-scription, health insurance, hospital or other existing databases41. These databases could ideally be linked to extract information on drug benefits and risks under real-life condi-tions. Such studies can be done rapidly while based on millions of prescriptions and health outcomes. Yet the relatively young science of pharmacoepidemiology remains fraught with methodological problems42. This is perhaps unsurprising as, in the absence of randomization, physicians will allocate patients to different treatments in ways that give rise to confounding results when the outcomes of therapies are compared.

However, past failures should not lead regulators to abandon a potentially useful tool but rather to amend and refine what may be an under-utilized and powerful resource. In fact, regulators are currently taking a number of steps to harness the potential of this source of information for post-marketing benefit/risk assessment. The FDA has contracts for access to several large administrative databases

Box 2 | Conditional approval in the EU: sunitinib as an example

The first example of conditional approval (or conditional marketing authorization) in the European Union (EU) was sunitinib (Sutent; Pfizer) for the treatment of refractory metastatic renal cancer51. The approval was based on what was considered a reasonably likely surrogate end point (objective response rate) in two single-armed studies; that is, studies with a suboptimal trial design.

The studies were conducted in a homogenous population of progressive patients with a predictable outcome of the disease. The estimated proportions of responders were 36.5% (95% CI, 24.7– 49.6%) and 35.8% (95% CI, 26.8–45.7%) in patients previously treated with interleukin 2 or interferon-a, respectively. The European Medicines Agency’s Committee for Medicinal Products for Human Use considered this effect in terms of tumour shrinkage unprecedented, and recommended conditional approval in spite of the methodological shortcomings of the studies.

The company was requested to provide, within a relatively short time frame, evidence that treatment with sunitinib would also translate into prolonged progression-free survival or overall survival. The company subsequently submitted results demonstrating that sunitinib significantly prolongs progression-free survival compared with interferon-a for patients with treatment-naive metastatic renal cell cancer. Although that trial involved patients in an earlier stage of treatment, on the basis of pharmacological and biological grounds, these results were considered sufficient to conclude that comprehensive clinical data on sunitinib had been provided. Sunitinib was then switched from a conditional to a standard marketing authorization.

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Children with newly diagnosed Ph+ CMLDec 2002

Children with Ph+ CML, chronic phase, failing IFN-α therapyDec 2002

Adults with newly diagnosed Ph+ CMLDec 2002

Adults with Ph+ CML, chronic phase, failing IFN-α therapyNov 2001

Adults with KIT (CD117)+unresectable and/ormetastatic GISTMay 2002

Adults with unresectablerecurrent and/or metastatic DFSPSep 2006

Adults with newly diagnosed Ph+ ALLand adults with relapsed or refractory Ph+ ALLSep 2006

Adults with MD/MPDassociated with PDGFR gene rearrangementsNov 2006

Adults with advanced HES and/or CEL with FIP1L1–PDGFRα rearrangementNov 2006

Subpopulations

Dise

ase

cond

ition

s

Imatinib

Metastatic colorectal cancer (in combination with fluoropyrimidine treatment)Jan 2008

Metastatic colorectal cancer, first line (in combination with intravenous 5-FU/FA ± irinotecan)Jan 2005

Metastatic breast cancer, first lineMar 2007

Advanced or metastatic lung cancer, non-squamous, first lineAug 2007

Advanced or metastatic renal cancer, first line Dec 2007

Subpopulations

Dise

ase

cond

ition

s

Bevacizumab

for epidemiological research37, whereas the EMEA is in the process of establishing a European Network of Centres for Pharmacovigilance and Pharmaco-epidemiology (ENCePP43). One of the ENCePP’s goals is to coordinate electronic health-care databases existing in the European Union to support post-marketing benefit/risk assessments by enabling fast retrospective analyses of drug utilization and linking them to patient outcome data. Again, developing this capability is expected to enhance the confidence of the regulators and the public in early drug approvals.

possible future directionsIt is difficult to predict how the access dilemma will play out in a stakeholder environment that is characterized by

unrealistic hopes pinned on medicines coupled with growing risk-aversion and suspicion of the pharmaceutical industry. It may be anticipated, however, that some current trends will be amplified, and, hope-fully, new tools will allow the issue to be addressed.

We expect drug licensing to move further in the direction of life-cycle regulatory man-agement (“live licence”). The FDA was prob-ably the first regulatory agency to implement early and frequent interactions with industry in the 1980s and other agencies have followed since. However, most of this inter-action is still centred on pre-marketing development issues. In the future, planned industry–regulatory interaction is expected to also involve guidance on post-marketing studies for reasons described later.

We also anticipate wider use of condi-tional approval (or accelerated approval) and staggered approvals, possibly along the lines of the life-cycle of imatinib (FIG. 3). This will progressively blur the line between pre-marketing and post-marketing activities. It is expected that drugs will increasingly be approved initially for small (sub-) groups of patients who are expected to accrue the greatest benefit from the drug in order to justify a positive benefit/risk balance in the presence of a limited safety database. For this approach to be successful for non-HIV and non-oncology drugs, an unmet need for well-defined patient subgroup(s) will have to be demonstrated — and approved by regulators. Opening up this door is expected to stimulate real innovation and research in new pharmacological pathways.

Early approval for small(er) subpopu-lations will be aided by two independent developments: biomarkers and electronic prescription monitoring. First, the emergence of new theranostic biomarkers will enable the definition of patient subsets44. These biomar-kers would allow targeted drug development with earlier demonstration of a positive bene-fit/risk profile by way of smaller and shorter clinical trials. At the same time, theranostic markers may assuage concerns that regulators may have that the benefit/risk assessment may become negative after approval. This is based on experience that, once the drug becomes approved, its use is typically much broader than the clinical-trial population and the approved population, as the drug would be available on an off-label use basis. However, this concern will probably be addressed by a second development: the increasing use of electronic prescription linked to electronic health databases will allow third-party payers to monitor and restrict off-label use. As payers would not normally reimburse drugs outside the labelled indication, the authorized indication is expected to become far more important as a driver of prescription behaviour than it is today.

Among the new biomarkers, it is expected that genomic parameters will have an increasingly important role. In the field of oncology, for instance, this may encom-pass both tumour profiling to predict drug response and background genetic variability of patients to define subpopulations with optimal therapeutic benefit/risk balance. A good example for the latter is the use of HlA-B*5701 screening before administra-tion of abacavir as an antiretroviral, which decreases toxicity (hypersensitivity syn-drome) by a substantial margin. This trend forms the basis for personalized medicine

Figure 3 | staggered approval — the regulatory life cycle. A growing number of drugs are initially licensed for a small indication, or limited to a subset of patients within one narrowly defined pathology, even though their pharmacological activity suggests they could be useful for a wider target population and/or for a range of pathologies. The figure shows the stepwise widening of approved conditions for treatment with imatinib (Glivec/Gleevec; Novartis) and bevacizumab (Avastin; Roche/Genentech), both within a defined disease (along the subpopulation axis) and across different pathologies that share the drug’s pharmacological target (along the disease condition axis). Each box represents one distinct regulatory procedure; approved indications have been simplified for ease of readability. The examples illustrate how drug licensing is becoming an iterative process. Early access for those patients with a high unmet need is enabled on the basis of limited data, but with each additional (sub-) indication, new data, often from randomized controlled trials, contribute to the safety database, enabling a more refined benefit/risk assessment. 5-FU, 5-fluorouracil; ALL, acute lymphoblastic leukaemia; CEL, chronic eosinophilic leukaemia; CML, chronic myeloid leukaemia; DFSP, dermato-fibrosarcoma protuberans; FA, folinic acid; GIST, gastro intestinal stromal tumour; HES, hypereosino-philic syndrome; IFN-a, interferon-a; MD, myelodysplastic disease; MPD, myeloproliferative disease; PDGFR, platelet-derived growth factor receptor; Ph+, Philadelphia chromosome positive.

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but its major role will initially be felt in clinical trials for drug development. It is possible that an increased number of future clinical trials will encompass both a statisti-cal hypothesis of overall treatment effect and a hypothesis of treatment effect in a genomic subset. It has been argued that adaptive design approaches will be more efficient than a conventional non-adaptive approach in this regard45. While we are optimistic about the impact of new biomarkers for drug candidate selection, theranostic purposes or safety screening, we do not predict wider use of biomarkers as surrogate end points to accelerate marketing authorization for the reasons detailed above.

Considering the various pressures on regulators to reconcile the need for early access to life-saving treatments and for ensuring ‘safe’ drugs, it is speculated that the existing gap in regulatory requirements between drugs for life-threatening versus non-life-threatening conditions will widen even further (BOX 1). Along similar lines, less innovative products will also face higher hurdles. For example, the current debate on surrogate end points (see above) may make it difficult to approve new drugs on the basis of surrogate end points only, when there is already at least one drug available that has demonstrated its efficacy through hard end points.

A sharp increase in post-marketing clinical research activities will become a necessity to continuously refine the benefit/risk assessment, including real-life perform-ance of drugs. This will probably comprise not only more post-marketing interventional trials (that is, RCTs, including pragmatic trials) but also observational (pharmaco-epidemiological) studies. legal frameworks allowing explicit agreements on the conduct and assessment of such studies between health-care database owners, pharmaceutical sponsors, academic centres and the regula-tors are being set up both in the United States and the European Union. The live-licence approach will bring about a re-emphasis on learning–confirming cycles, in which the learning part will often be informed by new non-clinical and mechanistic studies, (unplanned) subgroup analyses from RCTs, patient registries or meta-analyses46. Of note, post-marketing research activities will not only lead to detection of new adverse effects, but also to reassessment of efficacy under real-life conditions (effectiveness) and of treatment-eligible populations47.

Increasing interaction and collaboration between regulatory agencies and health technology assessment (HTA) organizations

is another development we would cautiously predict for the near future. For many years, industry adopted the stance that the two processes should be kept strictly separated. However, there is growing awareness that this independent assessment of data comes at a cost, in that drug development has to satisfy the non-harmonized requirements of both regulators and HTA organizations, sometimes giving rise to near-parallel drug development programmes. At least one HTA organization, the UK National Institute for Health and Clinical Excellence (NICE) plans to offer early scientific advice to companies ahead of their Phase III clinical trials; this should run parallel to — and might therefore contradict — the advice already provided by regulatory authorities48. Moreover, early access to market granted by regulators would not translate into early access to patients if payers were unwilling to grant early (condi-tional) reimbursement. Against this back-ground, and considering that some domains of cost-effectiveness assessment are close to the benefit/risk assessment performed by regulators49, we believe that experts in HTA organizations will be progressively invited to play an advisory role in regulatory decisions and provision of pre-marketing and post-marketing guidance to companies. In a few years, we may even see early access decisions as a joint exercise between regulators and HTA organizations.

The development of new tools for early market access will also create a need for improved ways of communicating the benefit/risk assessment to the public. Under the current paradigm, industry emphasises the benefits of drugs, whereas regulators communicate the risks, and patients and consumers are left in the middle. Although regulators have been reticent to commu-nicate drug benefits, for fear of being seen as advertising drugs, this approach may have to be reassessed, and we would predict regulators to migrate in future from risk communication to more balanced benefit/risk communication. Both the FDA’s Critical Path Initiative and the EU’s Innovative Medicines Initiative have highlighted the need for pilot studies on optimizing the criteria and communication of regula-tory decision-making. On the other hand, industry will also be required to be more transparent about their products, including disclosure of all early safety concerns.

Some of the developments anticipated will raise the entrance barriers for new drugs and become a disincentive for drug development programmes. This would foil well-intentioned attempts to ensure early

drug access. A discussion of incentives to the research-based pharmaceutical industry is beyond the scope of this article, but we cautiously predict a call for linking further regulatory requirements to incentives to pharmaceutical companies, perhaps based on existing models that have created win–win situations. For instance, legislation in several jurisdictions for paediatric studies couples successful performance of certain studies to extended market exclusivity. Under current EU legislation, a MAH can seek an additional year of market protection for a new indication of an authorized product if the new use offers a “significant clinical benefit”. To demonstrate such a bene-fit, companies will, in most instances, need to provide data from active-controlled trials; that is, provide the comparative efficacy data required by health-care decision-makers50.

In summary, new regulatory approaches and methodological tools as well as more transparency of decision-making processes will help regulators address the dilemma over the right timing of drug approval, and strike the right balance between early access and preventing inactive or harmful drugs from accessing the market. Highly needed drugs may access the market even earlier than today, whereas less innovative medicines would face higher hurdles.

Hans-Georg Eichler and Francesco Pignatti are at the European Medicines Agency (EMEA), 7 Westferry

Circus, Canary Wharf, London E14 4HB, UK.

Bruno Flamion is at the Laboratory of Physiology and Pharmacology, University of Namur, Rue de Bruxelles

61, 5000 Namur, Belgium, and the Agence Fédérale des Médicaments et des Produits de Santé,

Place Victor Horta 40, 1060 Brussels, Belgium.

Hubert Leufkens is at the University of Utrecht, Sorbonnelaan 16, 3585 CA Utrecht, The Netherlands, and the Medicines Evaluation Board, Kalvermarkt 53,

2511 CB Den Haag, The Netherlands.

Alasdair Breckenridge is at the Medicines and Healthcare products Regulatory Agency (MHRA),

10-2 Market Towers, 1 Nine Elms Lane, London SW8 5NQ, UK.

Correspondence to H.-G.E. e-mail: Hans-Georg.Eichler@emea.europa.eu

Disclaimer: the views expressed in this article are the personal views of the authors and

may not be understood or quoted as being made on behalf of or reflecting the position

of the EMEA or any other regulatory agency, or one of its committees or working parties.

doi:10.1038/nrd2664 Published online 12 September 2008

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FURTHER inFoRMATionPublic citizen: http://citizen.org/hrg

All links Are AcTive in The online pdf

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