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Research, published in The BMJ, reports that half of new drugs introduced to the German healthcare system have no added benefit.
Dr Gillies O’Bryan-Tear, Chair of the Policy and Communication Group of the Faculty of Pharmaceutical Medicine, and Pharmaceutical Physician, said:
“We read with interest the publication from the Institute for Quality and Efficiency in Health Care (IQWiG), the German equivalent of the UK NICE, responsible for the health economic and “value added” assessment of new drugs proposed for use in their healthcare system. These reviews are conducted in order to determine whether treatment with these novel medicines will be paid for (reimbursed) by the German state or insurance systems. This activity is distinct and separate from the activities of the German national regulatory body (BFARM) or the European Medicines Agency (EMA) which assess medicines against the “three pillars” of safety, quality and efficacy. These agencies do not perform an assessment of a medicines place within a competitive healthcare environment, where new and older medicines are in competition for prescribed use. Pharmaceutical companies and other bodies who wish to license drugs in any country need to supply robust evidence relating to these three pillars. This usually results from many years of chemical, manufacturing, preclinical and clinical research, the whole process from bench to humans taking ten years, and sometimes more.
“Over recent years, governments have recognised the need for an additional health economic and/or “value added” assessments of new medicines, in order to evaluate what value (defined in different ways in different countries) the medicine has in the context of their own healthcare system. This process attempts to evaluate the cost of a medicine in relation to the benefit the medicine brings, often in comparison to established treatments. This is a complex area, and involves several assumptions about standard of care, which is, itself, often different in different national systems.
“As the objectives of these two types of assessment are entirely different, the nature of the ‘evidence’ required may also differ. While the drug regulators determine safety, quality and efficacy, demonstrating that the drug does work, the other assessments by NICE and similar agencies in other countries assess whether it adds enough value to justify the proposed cost of paying for it, within the constraints and demands of their national systems.
“It is unfortunate that the authors do not make the above distinction clear in their article. For example, by heading one section “No Evidence of Added Benefit for most new drugs”, the reader could be forgiven for thinking that this means that the drug itself is ineffective. However, in fact, the drugs are undoubtedly effective but using the criteria for value added chosen by their agency, many new drugs do not satisfy their particular test and therefore treatment with these medicines may not be reimbursed.
“Regrettably, the criteria which the authors used to assess medicines are not provided in the article. For example at Table 1 under the section “No proof of added benefit” the authors simply state, for one drug, “No significant effects” and for another “no relevant studies: only placebo controlled studies available” – overlooking the fact that many existing therapies were first demonstrated to be effective in placebo-controlled studies. For other examples in their table, they provide the endpoints they have relied on, but they dismiss, by implication, any oncology trial for which overall mortality data are not available. On this criterion, Rituximab, Glivec and countless other highly effective – and life-saving – drugs would never have been made available to patients. The first Rituximab study was an open label single arm study in lymphoma, using response rate as an outcome, and was deemed sufficient at the time to approve the drug because of the transformational outcome observed compared to historical outcomes in patients treated with existing chemotherapeutic regimens. Additionally, they do not appear to consider an improved safety profile for a treatment of similar efficacy to be of benefit for patients. Many patients – and many doctors – would disagree.
“There are several inconsistencies in the numbers between various sections of the article: in Box 1 the authors state 56/216 medicines had major or considerable added benefit. In para 2 of page 2 the number is 54/216. In the Figure the number is also 54, but the distribution between Major and Considerable benefit (22 and 32) is completely different from the data in the Box (1 and 55 respectively).
“The authors make a valid point that the post marketing studies required to further support proof of efficacy in newly approved drugs, are not always completed or at least followed up adequately by the regulators: this is a matter for the agencies. However, there is at least one example of a drug which was approved but subsequently withdrawn when post marketing studies failed to confirm efficacy.
“In the final part of their interesting paper, the authors speculate on various ways in which the drug approval and development process could be improved, including, inter alia, the review of all development pipelines in companies by governments, to determine whether national priorities in health care are being addressed: and if they were not, mandating changes in research priorities within those companies. However, there are very few examples where government mandated policies or actions (in contrast to large NGO’s like the WHO and the Bill and Melinda Gates Foundation) have produced new or innovative drugs.”
Prof Ken Paterson, Honorary Senior Research Fellow at the Faculty of Medicine at the University of Glasgow and Former Chair of the Scottish Medicines Consortium, said:
“It is completely true that most new medicines offer little or no clinical benefit over existing treatments, or that any benefits are restricted to sub-groups of patients and not large patient populations. While having an impact on the disease they are trying to treat, they are often no better than the medicines we already have.
“It’s really important to distinguish between the roles of healthcare systems and the regulators in how they assess new medicines. Healthcare systems in all countries need processes in place to identify the clinical benefits of new drugs, which is what NICE, the Scottish Medicines Consortium and Institute for Quality and Efficiency in Health Care aim to do. In contrast, the licensing process at the European Medicines Agency requires medicines to demonstrate safety, quality and efficacy; demonstration of clinical benefit over existing therapies isn’t necessary, which is why medicines with minimal added value get to the market.
“Understandably, patients want access to medicines that can help them as soon as possible. However, pressure to speed up the drug development process means that more new medicines are coming to the market with less evidence of added clinical value, because we don’t have the research data. This has a negative impact on patients and the healthcare system, as clinicians can’t accurately advise individual patients whether the new drug is better than existing treatments for them.
“Pharmacologists and clinical pharmacologists are best placed within healthcare systems to lead assessments of added clinical value; they are well used to exploring differences between effects on diseases and effects on patients. The EMA can answer the question “Can a new medicine be licensed?”; clinical pharmacologists can help answer the question “Should it be used?””
Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine (LSHTM), said:
“This paper shows that more than half of newly marketed drugs in the German healthcare system have not been shown to have clinically meaningful benefits in terms of the most important outcomes. Drugs are often licensed on the basis of biochemical tests intended to predict the effects of a drug on clinically important outcomes. These tests may sometimes not be reliable or may predict less relevant outcomes. For example reduction in blood sugar may show a drug used in diabetes to have a potentially beneficial effect, but this blood sugar reduction may not have been checked to see if it results in clinical benefit such as reduced heart disease or mortality, where you’d need a much larger study and bigger follow up to find out if it performs better or worse than current drugs.
“Carrying out the necessarily larger trials prior to marketing is an obvious solution. But, under the current system would be more expensive and slower. Increasing the price of drugs and delaying their use in patients would be the result, but it may or may not be a price worth paying.
“Requiring comparative efficacy over existing treatments would require major changes in EU and UK law. The regulatory agencies operate under current law; it is a political, not a regulatory decision to change the system.
“These findings, while strictly restricted to Germany, would probably be similar if the study were carried out in the UK. The paper comes from the German equivalent – IQWiG (Institute for Quality and Efficiency in Health Care – of the National Institute for Health and Care Excellence (NICE), the UK body which gives advice on value for money of new drugs, based on clinical and quality of life outcomes. NICE do not recommend use of all newly marketed drugs, and they provide the UK population with a very valuable service. It should also be noted that IQWiG work in a different way and does not use the same criteria as NICE.”
Prof Justin Stebbing, NIHR Research Professor of Cancer Medicine and Medical Oncology, Imperial College London, said:
“Showing benefits of what we do, or cost-effectiveness are now a really important part of health policy and as a doctor treating patients it’s important to do one’s best for patients and their families. It’s very unusual for regulatory authorities to approve drugs without benefits but sometimes in some diseases benefits can be hard to quantify and in other cases a small benefit might be meaningful and contribute to the totality of good outcomes as part of multi-disciplinary care. We’re moving towards personalised medicine which means treating the right person at the right time with the right disease with the right drugs and for cancer, we’re now understanding it’s hundreds of diseases. Each one might be treated differently, but the benefits of treating a small proportion of patients for those might be much higher, without effecting the entire patient population. For example, in cancer a drug may not show a survival benefit because patients may receive the trial drug later on once approved, but the drug may help shrink the cancer and reduce symptoms associated with it, delay the time it takes to get worse, which can be very important.”
Prof Saad Shakir, Director, Drug Safety Research Unit (DSRU), said:
“Truly innovative medicinal products (genuine first in the class) are few and far in between. Most products that come to the market are the so called me-toos. Me-toos claim to be better than the original in terms of efficacy, safety, tolerability or price. There are cases where the improvements are significant, however, in most cases the advantages are marginal. If the new product is not better, healthcare systems ought to take advantage to put pressure on the company for pricing.
“Increasing numbers of products are biologicals (large protein molecules, such as monoclonal antibodies) where the new product (unless it is a copycat biosimilar) is likely to offer a therapeutic advantage.
“If products sell well, companies are reluctant to conduct post- marketing studies, usually the pharmaceutical companies’ policies when products are selling well are why rock the boat and do post marketing studies unless they are demanded by regulatory authorities or health technology assessment bodies.”
* ‘New drugs: where did we go wrong and what can we do better?’ by Beate Wieseler et al. was published in The BMJ at 23:30 UK time on Wednesday 10th July.
DOI: 10.1136/bmj.l4340
Declared interests
Dr Gillies O’Bryan-Tear: I have contributed to the approval of multiple new medicines in several therapy areas by US and Eu regulatory bodies, and also been responsible for applications for the reimbursement of new medicines by the UK NICE (National Institute for Health and Care Excellence).
Prof Ken Paterson: Prof Paterson is Former Chair of the Scottish Medicines Consortium. He also works helping pharmaceutical companies to demonstrate the added value of their medicines to NICE, SMC and IQWiG.
Prof Stephen Evans: “I was a member of the Drug Safety Committee at the European Medicines Agency until 2018, and currently act as an advisor to the UK Medicines and Healthcare products Regulatory Agency on some issues.”
Prof Saad Shakir: No conflict of interest.
None others received.