Importance of clinical trial transparency

As part of its Clinical Trial Transparency initiative, the European Medicines Agency (EMA) mandated a requirement for clinical trial sponsors to prepare a summary of the results of every study written in language understandable to patients and others not in the pharmaceutical industry. Regulation CTR EU No 536/2014 obliges the company to produce this summary of results for the lay audience one year after the end of the trial in the EU. This requirement was planned to take effect in 2018, but seems likely that it will not be implemented until 2019. The pharmaceutical industry is aware of this coming requirement and serious discussions are occurring as to how best to respond to this challenge.

Overall, CTR EU No 536/2014 is a positive development and is a welcome chance to deliver clinical study results to the general public, especially patients. The requirement to prepare a summary of the results of every clinical study in a form that can be understood by anyone is a major step forwards in transparency, an opportunity to explain drug development, and to increase public awareness and understanding of the industry. However, there is a danger that this opportunity will be missed, either through lack of clarity in the requirements, or because writing for a lay audience is notoriously difficult, and so companies may be tempted to fulfil the letter, rather than the spirit, of the regulations. A lay summary describes a single study – there is no context of wider clinical development to enable the reader to properly evaluate the benefit/risk of a drug, and there is a danger that ambiguity in the new regulation may result in similar misinterpretation.

There are ten suggested headings for the CTR lay summary, for some of them the information to be added is very clear and obvious, but for others, companies must make their own interpretation.

Clinical trial identification

How helpful this section will be for patients is questionable. If the title is complex, a simpler title should also be added, but care must be taken that when complex language is simplified that it does not become misleading.

Name and contact of sponsor

This section is self-explanatory.

General information about the clinical trial

The methods section should be straightforward, but some companies believe that results for every single parameter should be mentioned in the methods. By itself, this may be no bad thing, but these ‘summary sections’ can mushroom into long lists of numbers and multipage tables.

Population of subjects

There can be huge numbers of inclusion and exclusion criteria, and long lists of complex terms can be very difficult to understand. Which criteria should be included if the lists are too long?

Investigational medicinal products used

The general public are unlikely to be familiar with generic names, and brand names can be different in different countries.

Description of adverse reactions and their frequency

Discussing adverse events (AEs) can be very challenging. Even the term ‘adverse reaction’ can cause confusion, and the seriousness and frequency of each reaction should be explained and described. Most AEs are described in Medical Dictionary for Regulatory Activities (MedDRA) terms, and so will need to be explained in lay language. The general challenge is to communicate benefit/risk information.

Overall results of the clinical trials

The results of the trial should be described, but this can be very difficult considering that health numeracy levels (the ability to understand and interpret numbers related to health information) in the general population are even lower than those of health literacy.

Technical terms – such as number needed to treat, pharmacokinetic parameters, confidence interval and so on –.are particularly difficult to explain to a lay audience, and even more difficult for them to interpret.

Tables and graphs that are easy for those of us in clinical research to understand and interpret due to the familiarity that comes with long and repeated exposure may not be so straightforward to the public.

How confident can we be that patients will be able to correctly interpret at first glance a shift table, Forest Plot, or Kaplan-Meier survival analysis? Presenting only the top level or main results can also be interpreted as a ‘cherry-picking’ approach, so a balanced, true representation of the results must be given.

Using statistical terms to explain how much ‘trust’ the reader can place in a result can increase the perception of risk.

Finally, there is the issue of what information to present. For efficacy results, a way must be found to discuss the difference between the interpretation of primary and secondary analyses, to say nothing of exploratory analyses.

Giving the public complex information does not help them to make decisions – especially if the information is numerical. It also calls into question the value of disclosing complex clinical trial results without context and explanation (neither of which is currently mandated by the regulation).

How can we communicate that clinical studies are designed with statistical power such that statistically significant results for the primary analysis indicate a clinically relevant effect, whereas for secondary analyses the interpretation is weaker and more complex? This is a challenge even for a scientifically literate audience.

Safety results might appear at first glance to be easier to communicate, but there are challenges here as well. Most adverse event results are given with a percentage indicating frequency.

The accuracy of these frequencies, however, is very strongly dependent on the sample size; accuracy drops sharply in small studies, but how much it drops and the relative importance of different events can be very difficult to explain.

Comments on the outcome of the clinical trial

This should be an overall summary of the results and their implication. However, it should be unbiased and not sound promotional. It is hard to describe positive results so that they are not interpreted as promotional, but this is an excellent opportunity for companies to describe how clinically meaningful the results are.

Indication if follow up clinical trials are foreseen

This section should explain if and when more studies will be done on the drug.

Indication where additional information could be found

This tenth and final section is self-explanatory, but links could also be given to more general sites, such as plain language dictionaries.

The path to understanding

These challenges are not insurmountable and have not been ignored. EMA has ongoing consultations with industry and patient groups to try to improve the guidance for industry in communicating with the layperson. There are also companies offering testing services to allow testing of lay text with its audience.

The continued dialogue between regulators and industry around the issues of transparency and communicating with the public offers the chance to develop guidelines that can lead to summary documents that truly aid understanding of clinical research, and improve trust in and perception of the pharmaceutical industry, rather than just add yet another document to the large pile of submission requirements for clinical research.

It would be a tragic waste of an opportunity if these new regulations simply led to the addition of another overly long and impenetrable summary of clinical study results. Instead, everyone involved in either the writing or the designing of templates and procedures for lay summaries should invest time and resources in making sure that the resulting documents help, rather than hinder, understanding.

The pharmaceutical industry has few opportunities to communicate directly with patients in Europe, and so it would be good to remember the reader when producing this document, and see the lay summary of the CSR not as yet another regulatory hurdle to be mechanically created and filed to gather dust, but rather as a unique chance to expand the science-public interface, and perhaps improve the general understanding and acceptance of science into the bargain.