How Much Information for Informed Consent?

Meetings of the European Forum for Good Clinical Practice (EFGCP) tend to be well attended. This group has, from its modest beginnings much more than a decade ago, built for itself a reputation that guarantees attention, and attracts respect. But when an EFGCP meeting is spectacularly well attended, there must be something special on the agenda.

Peter O’Donnell

This was clearly the case at the group's meeting in Brussels in January. A meeting positively bursting at the seams. What was it that had brought together so many of Europe's (to say nothing of those from beyond) clinical trials community? An important subject, obviously. It is not enough to nod vaguely at that suggestion. The subject was indeed consent—but informed consent. No one was seen nodding off during the proceedings, either. This is an issue that has been bubbling away underneath so much of the anguished discussions of European clinical trials regulation since before even the formation of EFGCP. It underlies so much of the discussion of good clinical practice. It raises a raft of questions fundamental to the very nature of clinical trials. And it is still far from resolved.

In its own admirable fashion, EFGCP will doubtless publish its own record of the conference and its conclusions. This column does not wish to steal its thunder. But it is worth pausing for a moment to reflect on why the subject remains so sensitive in Europe.

The central concerns are linked both to efficiency and to ethics—an uncomfortable emulsion at the best of times. Hesitations, divergences, and uncertainties over informed consent bedevil trials large and small, hampering authorization or protocol approval, and generating delay and costs. But at the same time, the efforts —indeed on occasions contortions—that sponsors are put to frequently raise the question of cui bono—who is it all being done for? As Detlef Niese of Novartis remarked, the risk is that the rules are reducing this refined concept of informed consent to just a matter of obtaining a signature, when it should be a matter of understanding. Or as Harry Bleiberg of the Institut Jules Bordet in Brussels put it: "Is the patient information sheet and informed consent form protecting the patient—or the sponsor?"

There is a nexus of potential conflicts of interest, as Bleiberg illustrated with his elaboration of who is involved. The patient, of course, can be seen as blameless: he or she needs an effective treatment, with minimum side effects and risks, and maximum quality of life and support in case of problems. The sponsor, however, wants maximum reliable data and minimal costs, but also wants rapid accrual—not always consonant with obtaining full informed consent. The investigator also needs patients—and is subject to the same conflicting pressures. The insurance company has interests as well: of course it wants to limit damage to patients, but it also wants to limit liability and consequently possible payments for damages. And even the hospital administration at a trial site may have less than a totally disinterested approach, since it benefits from the revenues generated by hosting trials.

EFGCP was careful to put together a program that reflected the broad range of interests provoked by informed consent. "This topic cannot be discussed and improved without all parties involved in the process," said Ingrid Klingmann, the EFGCP Board Chair. So, quite deliberately, EFGCP sought a partnership with researchers and ethics committee members and patient representatives in the creation and execution of the meeting.

Petra Knupfer, a leading German Ethical Committee Member, put the same dilemma slightly differently, but with the same force. The patient is seeking help, and needs time to make a decision on the merits of enrolling in a trial. But the investigator must deliver information, and to do this, a signed document is needed—and time is at a premium.

Overloaded consent requirements

That meticulous lawyer from the Institute of Health Law at the University of Neuchâtel in Switzerland, Dominique Sprumont, brought his forensic focus to the issue: "The ethics review process and informed consent requirements are held by some researchers to have the negative impact of delaying or even halting the research agenda." He recognized that informed consent has become overloaded with rules and functions—many of which should, he said, be scrutinized to assess their real necessity. Characteristically, he drilled down expertly to pose the basic question of why informed consent is needed, and urged that rather than increased dependence on rules, the emphasis should be on clarifying the responsibilities of everyone involved.

The risk of losing sight of the wood for the trees was underlined by Denis Lacombe of the European Organization for Research and Treatment of Cancer. The complexity of trials has led to long and often multiple patient information sheets and informed consent forms, with more administrative and legal information than scientific content. "The final document can miss the goal," he said, "by protecting the sponsor rather than informing the patient."

EFGCP itself posed some of the challenges in its own pre-conference briefing material. "There is widespread concern that the information we give research participants isn't fit for purpose. Information sheets are now too long, incomprehensible and don't match the risk of the study," it said.

The ethics committee of Vienna Medical University has done some research into the topic. It concluded that more than 95% of the information consent forms of commercially sponsored studies are insufficient when first presented, because of their length, their language, or legal compliance. Between 2005 and 2011, the average length of forms submitted to the committee grew by 40%, from 12 pages to 17 pages. Many suffered from imperfect texts, partly because they were often translated word-for-word from English (frequently in line with company policy), rendering them rebarbative to the reader, and partly because they featured numerous technical terms and foreign words. And many failed to meet local law on issues of insurance, liability, reimbursement, or frequency of pregnancy tests.

Annette Rid of the Institute of Biomedical Ethics at Zurich University dared, as an agent provocatrice, to float a contrary concept—that far from being too onerous, standards for informed consent may not be demanding enough.

The conclusions from the meeting will inform EFGCP's reflections on improvements, and may well play into the next round of lobbying in European circles on the shape that regulation should take for clinical trials. With the prospect of a major revision of the European Union's current rules being proposed in the course of this year (the latest rumors are that September is the likeliest date), informed discussion of informed consent will be a valuable input to the thinking of EU officials as they refine their draft legislation.

Regulatory reshuffles

Meanwhile, in the bureaucracy of Brussels (and its satellites), the new year has brought in some changes of people and positions—many of them with a significant influence on the world of clinical trials. The European Commission has split its pharmaceuticals unit in response to the massive workload it faces in regulating medicines. Stefano Soro, an Italian official previously responsible for consumer safety, has become head of a new unit entitled Medicinal Products—Quality, Safety, and Efficacy in the commission's health and consumer affairs directorate general. This will be dealing with standard setting in respect of clinical trials, falsified medicines, pharmacopoeia, and veterinary medicines regulation. Stefan Fuehring, who is in charge of the revision of the clinical trials directive, is moving to the new unit.

Patricia Brunko remains head of a now-reduced unit entitled Medicinal Products—Authorizations, EMA. This will be dealing with all matters related to authorization of medicinal products, including pharmacovigilance, and the European Medicines Agency.

Andrzej Rys, the Director for Health Systems and Products, and responsible for both these units, says the changes have been made "in order to reinforce the capacity of the commission to respond to the intensity of the demands on the previous unit." He said "the changes are not intended to affect stakeholders, as they are a matter of internal organization."

New staff have taken on responsibility for pharmaceuticals in the other commission department with a direct involvement in medicines, the enterprise and industry directorate-general. Following the departure of Giulia del Brenna late last year from the unit entitled Food and Healthcare Industries, Biotechnology, another Italian has been appointed to replace her as head of unit. It is Salvatore D'Acunto, who was in charge of passenger rights in the European Commission until now. It will be his job to pick up the work on the long-awaited revision of the so-called transparency directive, governing national pricing and reimbursement procedures for medicines. He will also be supervising the numerous working groups on access to medicines and corporate responsibility that enterprise and industry commissioner Antonio Tajani set up last year.

The European Medicines Agency has also modified its management chart. Three sections now report directly to its new Executive Director, Guido Rasi: human medicines development and evaluation, under Patrick le Courtois; patient health protection under Noël Wathion; and veterinary medicines and product data management. The sections responsible for information technology and communications and for administration now report to the new Deputy Executive Director, Andreas Pott.

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.