The complexity of the therapeutic environment

The authorisation and the life of a drug are dictated by a number of stakeholders. If it is possible to list (in decreasing order of importance) the responsibility to provide a drug to a patient, it might be as follows:

Legislative bodies – the law determines the general framework of the pharmaceutical environment. The European Medicines Agency is responsible for the regulation and approval of new drugs in Europe, and publishes three documents:

  • the leaflet for patients
  • the Summary of Product Characteristics for physicians
  • the European Public Assessment Report describing the pathway that led to approval.

National agencies usually have only a minor role in the approval of drugs (today mostly generics) but are very important for reimbursement by national health services.

Scientific societies – these are generally responsible for drafting guidelines and in some cases must exert pressure to obtain rapid approval of drugs (e.g. for anticancer drugs)

Prescribers – whether in hospitals or primary care, prescribers have the final decision of what to give the patient

Patients or consumer associations – these groups usually have very limited influence.

All these stakeholders are influenced by two forces:

  • the pharmaceutical industry, which is obviously interested in selling as many medicinal products as possible at the highest possible price
  • the national heath service, which funds the provision of only essential drugs to patients at the lowest possible price.

Pharmaceutical companies, either directly or through their lobby groups (e.g. the European Federation of Pharmaceutical Industries and Associations in Europe), have the ability to influence all stakeholders. Their support of scientific societies, marketing to prescribers and the financing of patients’ associations, as well as the media, is pervasive and extremely effective. In contrast, information coming from the national health service is, in general, relatively scarce. This creates an asymmetric system driven by economic interests, while the national heath service has limited influence.

The imbalance between the industry-funded information and independent information has led to distortion in the conception of medicinal products, which are becoming consumer goods rather than therapeutic tools.

How drugs satisfy patients’ needs

Each year the US Food and Drug Administration authorises about 60 new chemical entities to be marketed, and the European Medicines Agency authorises about 30 new entities. The importance of these new products is very limited since they are often drugs belonging to an existing therapeutic class, with only small chemical changes. In addition, in the last decade there has been an increase of biopharmaceuticals (obtained by DNA-recombinant techniques, such as monoclonal antibodies).

The analyses to date indicate that most new medicinal products are not necessary. One French study showed that out of 961 drugs approved in the period 1999–2008 about 49% brought nothing new, 11% were ‘not acceptable’, and the others could offer some benefits, but only 2% provided any real advantage.1 Another study analysed the improvements in quality of life, expressed as quality-adjusted life years (QALY), induced by 281 new medicinal products. Only 12% induced more than 1 QALY, while 51% induced less than 0.1 QALY.2

Some confusion arises depending on the parameters used to establish the progressive value of therapy. A percentage can be misleading, and it is better to express the advantage in absolute terms. A clear idea about the value of a drug can be estimated from the number of patients that must be treated with a given drug in order to obtain a positive outcome in terms of reduced mortality or morbidity – the number needed to treat (NNT). The same can be done using the number needed to harm (NNH), i.e. the number of patients that must be treated to observe an important adverse event. The ratio of NNT to NNH constitutes an attempt to identify a ‘therapeutic ratio’.

A fair evaluation of medicinal products should not only be quantitative, but should also address the relation between patients’ unmet needs and efforts to make drugs available to meet these needs. For instance, bacterial resistance to antibiotics has not been followed by the development of new antibiotics effective against resistant microorganisms. Similarly, there have been no truly new agents for mental disorders (psychotropic drugs) in the past 30 years, and several important multinational pharmaceutical companies have abandoned this field of research.

A recent study pointed out the discrepancy between the burden of a given disease and the number of drugs available. Epidemiological data indicate that while there has been a considerable decline in mortality due to cardiovascular diseases, in the field of cancer (namely breast and colorectal cancers) in the last decade there has been less improvement over previous decades despite the number of drugs approved.

Orphan drugs merit special mention. In the last 10 years only 63 drugs have been approved by the European Medicines Agency for the 6000 rare diseases awaiting treatment. In some cases the evidence of a favourable benefit–risk ratio is very doubtful. Similar considerations are offered for the lack of new drugs for the neglected diseases of people in developing countries.

Bias in randomised controlled clinical trials

The scientific literature has recognised a number of biases that affect randomised controlled trials. In general these tend to magnify the benefit of a drug and minimise adverse reactions. All these biases lead to poor innovation.

Abuse of placebo

It is obvious that a comparison with placebo rather than with an active comparator allows better appraisal of a drug’s benefit. In this respect there is considerable disagreement between the Declaration of Helsinki and the rules issued by the US and European regulatory agencies. There are three different types of abuse of placebo:

  • direct comparison with placebo (two-arm studies)
  • use of placebo in an add-on design
  • the three-arm design (placebo, comparator, new drug).

In all three cases not using the comparator (when available) can harm patients in the placebo group because they receive no treatment or treatment that is less than optimal. Examples of this bias include:

  • the recent direct comparison of placebo with drugs developed for multiple sclerosis (e.g. cladribine, fingolimod, laquinimod)
  • the combination of metformin with a new antidiabetic drug where placebo is used, despite established standard treatment combinations of two antidiabetic drugs
  • the comparison of antidepressants where placebo is not necessary if the trial is designed to detect superiority.


Selection of the comparator is very important because it can affect the evaluation of the new drug. Ideally the best standard should be used, at the best dose and duration of treatment. In practice these variables are often selected in order to favour the new drug. For instance in the case of rofecoxib, comparison with naproxen would have detected the cardiovascular adverse effects induced by rofecoxib. In another example, tacrolimus was shown to be superior to cyclosporin only because cyclosporin was used at suboptimal doses.

Non-inferiority trials

In this type of trial, investigators test the null hypothesis that a new drug is worse than the active control (standard therapy). When they can reject the null hypothesis, they accept the alternative, the new drug is not worse, but do we really need non-inferior drugs? Often the difference for acceptance of non-inferiority may be 25–50%. Patients rarely receive clear information in the informed consent form about the significance of this experimental design.

Surrogate end points

Frequently the evaluation of a drug is not based on therapeutic advantages for the patients, but on indicators that may indirectly reflect possible advantages. Examples are decreased blood cholesterol as a surrogate for reduction of myocardial infarction, decreased blood pressure as a surrogate for reduction of stroke, and decreased blood glucose as a surrogate for cardiovascular complications of diabetes. In some cases therapeutic end points are considered equivalent to surrogate end points, particularly when a group of drugs belong to a class with a similar mechanism of action.

However, since each drug has its own chemical structure, adverse reactions may in fact outweigh the benefit. Statins are an example. Rosuvastatin was approved for use on the basis of its hypocholesterolaemic effect, but simvastatin and pravastatin had already demonstrated protective effects against myocardial infarction. Cerivastatin was withdrawn because of toxicity. In another example, several anticancer drugs have been approved on the grounds that they reduce tumour volume, but with no evidence of improvement in overall survival or quality of life.

Composite end points

Where specific events are relatively few, it has become customary to group several events together. For instance death, myocardial infarction, stroke and coronary artery occlusion may be grouped as ‘cardiovascular events’. When a drug achieves a statistically significant decrease in a composite end point it is proclaimed that all the individual end points have been beneficially affected. However, the significance is usually driven by minor points that are less important therapeutically.

Fragile populations

New drugs are frequently tested on men rather than the population that will be using the drug, such as older people. Children are rarely recruited for trials, nor are women of fertile age. Furthermore, patients are selected for trials in artificial conditions, while in clinical practice patients may have multiple comorbidities and be taking several drugs already. Consequently, the trials may overestimate the drug’s benefits and underestimate its harms in clinical practice.

Publication bias

This term refers to the tendency to favour publications showing positive results rather than negative ones. This has created a number of problems in drug assessment. For instance, the selective serotonin reuptake inhibitors have been considered active in mild depression even though they are not different from placebo. Reboxetine is overall an ineffective and potentially harmful antidepressant when positive and negative trials are assessed together.3 The suicidal tendencies induced by antidepressant drugs in adolescents have not been well publicised.

Adverse reactions

The risk induced by drugs can seldom be detected during trials because they recruit too few people. Adequate postmarketing follow-up is therefore important. However, most drug withdrawals are instigated by pharmaceutical companies rather than the regulatory authority, indicating that appropriate follow-up by regulatory authorities does not occur. In addition, withdrawal is often considerably delayed, such as in the case of rofecoxib, cerivastatin, rosiglitazone, sibutramine, and rimonabant.

Some proposals for change

It is difficult to change the present system because all stakeholders have some vested interests. However, the present crisis may offer an opportunity to make some changes.

There are essentially three changes needed to the legislation:

The approval of a new drug presently requires only evidence of quality, efficacy and safety. It would be important to also require ‘added value’. This would abolish pivotal studies of non-inferiority and would require comparative studies in order to identify advantages over drugs already available on the market.

Confidentiality should be abolished, at least for pharmacological, toxicological and clinical data. There is no reason to maintain confidentiality because, for clinical trials in particular, the data belong to the patients. Without their generosity there would be no clinical trials.

The regulatory authorities should be funded from public sources. The European Union and its member states could recover their funding from industry in different ways.

These changes in legislation would result in stricter approval processes that allow only drugs that offer true innovation in therapeutic terms to be marketed (see Table).

Table - Regulatory evaluation of clinical trials




Kind of comparison


Superiority to placebo


Superiority to placebo



Non-inferiority to active comparator


Kind of comparator
(and its dosage)

Not always the most appropriate

The best available treatment

Outcome measure

Surrogate outcomes

Clinically meaningful outcomes addressing significant better and/or longer life

To avoid bias in trials, one of the two pivotal phase III trials should be carried out by an independent non-profit organisation.

Regarding adverse reactions, it is important to require ‘active pharmacovigilance’. At present the Committee for Human Medicinal Products, a technical advisory body of the European Medicines Agency, is responsible for the approval (or rejection), appeal and withdrawal of drugs. This creates a conflict of interest, since it is hard for the same body to exert contradictory functions. A separate committee should be responsible for monitoring for adverse effects over the life of a drug and making decisions about modifying the summary of product characteristics or withdrawing a drug.

Independent research must be promoted at the preclinical and clinical levels. There is a tendency to translate the effects of a drug too fast from laboratory to humans. Although this can be done on healthy volunteers under specific conditions, thorough evaluation is essential in vitro and in several animal species and models of human diseases. The action of antivivisection groups poses a serious obstacle to the extension of laboratory tests to animals. In addition, excessive bureaucratic rules hamper the development of knowledge useful to understand drug actions. It must be recognised that the pharmacological effect in animal tests is frequently too small to suggest real therapeutic action. The example of some anticancer drugs is pertinent in this respect.

Investigator-driven clinical trials organised by non-profit organisations should be encouraged by making available funding and infrastructures, particularly for international collaboration on large clinical trials, and trials for rare and neglected diseases. For the past two years, special topics for independent trials have been supported under Framework Program 7 in Europe. In Italy a special law has established a research fund by taxation of 5% on all promotional expenses (except salaries) borne by pharmaceutical companies.

For five years there have been annual calls for investigator-driven clinical trials comparing drugs for the same indications, addressing new indications for old drugs, or testing orphan drugs. An international peer review assigns funds to the selected proposals. The independent research is not only useful for better evaluation of drug toxicity and activity, but also to optimise doses and duration of treatment. In some cases equivalence of drugs with different prices can allow savings on drug expenses. Independent trials should also aim to involve practitioners in order to evaluate drugs in current clinical practice, particularly in the elderly and children.

In order to avoid repetitive studies and delay in developing new indications or contraindications, before starting any new trial it is important to undertake a systematic review or a meta-analysis of trials that have already been done. Unfortunately, a number of trials are still done without any preliminary review. These studies waste resources and expose people to undue risks. In Europe a six-month patent extension is offered as an incentive to carry out trials in children. In some cases it would be less expensive for the national health service to fund these trials, providing the results are recognised by the regulatory authority.

The present legislation for randomised controlled trials (through Good Clinical Practices) does not distinguish between the requirements necessary for a new medicinal product and those for independent research using drugs already on the market (e.g. for comparison, optimisation or new indications). These studies should be less burdened by official requirements. The risk of a given trial should dictate the need for insurance, the grading of monitoring and the reporting of adverse reactions.

In Europe the European Clinical Research Infrastructure Network has been created to assist international trials by providing the necessary information and helping to deal with national differences in clinical trials requirements.


Following Professor Garattini’s presentation, participants raised the following key points in discussion:

  • The concept of introducing a 5% levy on drug companies to fund investigator-initiated research was seen as a good idea. This money could also be used to fund research that would provide reliable information about the effectiveness of drugs in those high-need population groups that are likely to benefit from the drugs (e.g. children, women, the elderly).
  • Guideline developers must constantly assess whether the study design of a trial is applicable to their target populations.
  • There is a lack of trials evaluating non-drug interventions, such as physical activity or dietary changes, which may be just as effective as drug therapy for managing disease and improving health outcomes.
  • A number of complementary and alternative therapies are actively advertised and promoted as having a therapeutic benefit. While not all of these therapies may be dangerous, there is no requirement to demonstrate their efficacy in rigorous trials, so there are no data about their effectiveness. There should be consideration of introducing the same regulatory framework for the approval of these products as there are for registered drugs.
  • Off-label use of products is hard to monitor and evaluate.
  • There is a need to engage more closely with the public and consumers to get input into the topics of greatest concern for them and incorporate this information into the research agenda.

Professor Garattini explained the Mario Negri Institute's policy on competing interests (see Appendix 2 for details).