Over the last few years, the way clinical trials have been conducted in Europe has developed rapidly. Not only is this because of the implementation of the Clinical Trials Directive 2001/20/EC, but also the Data Protection provisions in Directive 95/46/EC have needed to be reflected and the trials on biological Investigational Medicine Products, with novel forms, and modes of action has meant that there has been consideration and debate regarding how trials should be conducted. This has been particularly high profile since 2006 when a First-In-Man (“FIM”) trial of an “immuno modulator” compound (TGN1412), a novel monoclonal antibody developed to treat auto immune/inflammatory diseases and haemato-oncological malignancies, resulted in unprecedented and unexpected toxicity that seriously injured six healthy volunteers. The results triggered a widely publicized scientific debate, firstly in the UK and thereafter more broadly, and resulted in the publication of guidelines regarding the conduct of trials involving such products. The tragedy also provoked controversy in the lay community over the principles of design and content of clinical trials as well as the use of FIM studies, and differences between development of biopharmaceutical products and pharmaceutical products. After a brief introduction to the EU clinical trial regime, these two issues will be given further consideration in this paper.
Directive 2001/20/EC – The Clinical Trials Directive (“CTD”)
The CTD establishes rules and guidelines for the approval, conduct and management of clinical trials in the European Union. Its goals are to protect clinical trial participants and to improve and standardize clinical trial procedures, whilst requiring monitoring of adverse reactions that occur during clinical trials. Prior to the introduction of the CTD, the EU followed the International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use (“ICH”). The implementation of ICH varied from Member State to Member State and the Commission were keen to regularize and harmonize the conduct of clinical trials. The CTD built on and developed the ICH standards and describes how these standards should be incorporated into clinical trial practice within the EU. Further guidance is provided in Directive 2005/28/EC, which provides further detail, particularly in relation to the implementation of good clinical practice (“GCP”) and good manufacturing practice (“GMP”).
In accordance with the EU constitutional law, each Member State is obliged to implement the provisions of these Directives into their respective local laws.
Data Protection
One of the key tenets of the clinical trials regulatory regime is the protection of subjects. This must be considered in the context of the Data Protection Directive 95/46/EC “on the protection of individuals with regard to the processing of personal data or the free movement of such data.” This Directive was introduced to enhance the development of a “frontier free internal market” and, in the days of the “information society,” to increase the cross-frontier flows of personal data between Member States of the EU. In order to remove potential obstacles to such flows and to ensure a high level of protection within the EU, the data protection legislation has been harmonized between Member States. The Data Protection Directive regulates the processing of personal data, whether that processing is automated or not and determines that personal data should not be processed at all unless certain conditions within the categories of transparency, legitimate purpose and proportionality are met. These additions are satisfied as follows:
- Transparency - the data subject has the right to be informed when his personal data are being processed, and the purpose there for.
- Legitimate purpose – personal data can only be processed for specific explicit and legitimate purposes and may not be processed further in a way incompatible with those purposes.
- Proportionality – personal data may be processed only in so far as it is adequate, relevant, and not excessive in relation to the purposes for which they are collected and/or further processed.
So How Does This Become Reflected in Clinical Trials?
The Sponsor of a clinical trial is most likely to be considered the “data controller” who bears the responsibility for compliance with data protection not only in relation to the Data Protection Directive, but also the provisions in the CTD regarding informed consent. Data collected from trial subjects will comprise personal data, i.e., data that will be subject to the Data Protection Directive and most often, personal sensitive data which demands further care in processing. The rules cannot be circumvented by mere data anonymity because this activity equates to processing. Furthermore, subjects must give explicit consent to the process of any sensitive data and in giving that consent must be told what data is going to be processed, who is controlling the data, the purpose(s) for which it is being processed and the details of where it will be sent (e.g., to regulatory authorities). They must therefore be in a position to be able to give informed consent at the time that they sign up for the clinical trials. In addition to being told the forthcoming the subjects should be told more particularly:
- The aim of the trial
- Its significance
- The methodology for carrying out the trial and obtaining data
- The risks involved in undertaking the trial
- How long the trial will take
- That the subject can withdraw from the trial at any time
- Contact points for further information
But how can informed consent be determined in all circumstances when one is dealing with subjects or patients which may be incapacitated, partially or wholly, or too young to properly make such a decision. Furthermore, there is no definition of “consent” in the Data Protection Directive but there is some guidance in the CTD as to what steps to take. Since medical data is sensitive personal data and explicit and informed consent must be given, it is assumed that informed consent would be given in the knowledge of the possible consequences and the possible risks and benefits. However, it is unlikely that any person, even a fully compos mentis adult, could be 100% aware of all the risks and benefits.
Further issues arise in relation to clinical trials on minors. A minor’s wish to refuse or withdraw from a trial must be ‘considered’ but will not determine definitely whether they will be included in the trial. There can be no incentives or financial inducements to encourage a minor or his responsible adults to involve them in a trial and there has to be a direct benefit for his patient group to the extent that research which relates to the minor’s clinical condition can only be conducted in minor. The patient’s interest (which does not necessarily equate to obtaining the minor subject’s consent) must prevail and a pediatric expert will make comment to the Ethics Committee (who is responsible from an ethical point of view, the trial should go ahead) about the suitability of involvement of the minor subject in assessing the capacity if the minor subject to make an informed decision, its age, maturity and mental capacity will be taken into account an order to determine how cognisant it is of the trial and the circumstances surrounding the trial.
Similar problems arise in relation to incapacitated adults. Once again, their wish to refuse or withdraw will be considered, but may not be wholly influential. There can be no incentives or financial inducements to their entering the trial. In the case of severely incapacitated adults, for example, an unconscious patient who has suffered a stroke and who would benefit from being treated with a trial medicine, it is difficult to establish how they could give any sort of informed consent. Historically, clinicians have taken the view that if the research relates to a life threatening or debilitating condition of the patient the clinician can act as a responsible adult and decide what steps to take, provided that the patient’s interest prevails. However, under the more strict regime of the CTD, a responsible adult must be found before the trial or treatment can be undertaken and this has caused, on occasion, serious delay or cancellation of the involvement of the subject of a trial.
Best practice is that written informed consent should be provided with proof that it has been given freely (i.e., with no conditions such as “you must consent in order to receive the latest treatment”) and that the consent is specific and informed. Ideally, this document will include details of:
- Who gave the subject the information
- What form the communication took
- What information was provided about the purposes of the research, the subsequent processing of the data and to whom else it would be disclosed.
How the subject signified their consent should also be recorded. In these electronic days it is likely that there will be a web-based consent. However, not all patients are comfortable with computerized information systems and providing proof of agreement can be a challenge: if their terminal is in a clinic should the nurse or receptionist be on hand to witness the patients click or typing. If however, the consent is given remotely, should passwords, biometrics or digital signatures be used to ensure that the level of proof is suitably high?
Clearly, the multifarious challenges in conducting a clinical trial in accordance with all prevailing Directives, Regulations and Guidelines have become ever more complicated in an increasingly regulated and electronic world.
Differences Between Clinical Trials Between Biopharmaceuticals and Conventional Pharmaceutical Products
Over the last few years, and particularly since the TGN1412 case referred to above, considerable review has gone into comparing the difference between biopharmaceutical and conventional pharmaceutical and how these should be handled. These differences arise out of their varying mode of actions (biopharmaceuticals comprise different amino acids and carbohydrates, in elaborate folds of matter and are both less stable, are subject to degeneration and less predictable than conventional pharmaceuticals) and their modes of manufacture (and the manufacture of biopharmaceuticals involves the manipulation of live cells). Because of the differing modes of action, standard tests may not be generally applicable for biopharmaceutical products, and therefore, care must be taken during transition from the preclinical phase to FIM clinical trials. Whilst the general principle regarding risk/benefit and risk/mitigation strategy must be maintained, new methods of assessing starting doses and dosing regimes have had to be undertaken. Whereas previously, the toxicity seen in animals was seen as directly relevant to its likely toxicity in humans, this is less likely to apply in biological material; therefore, rather than starting the FIM trial with the highest does thought safe, it is suggested that the lowest dose that is active should be the starting point. Furthermore, the clinical trial should not define the risks but the risks should dictate how the trial should be conducted; methods must therefore be adapted. The debate has resulted in the production of a new set of guidelines from CHMP – “Guidelines on Strategies to Identify and Mitigate Risks in First-in-Man Clinical Trials on Investigational Additional Products” - this document drew heavily on expert scientific group recommendations following the TGN1412 case including the following:
- Decisions on the strategy for pre-clinical development of a new medicine and experimental approaches used to assemble information relevant to the safety of FIM studies must be science based, made and justified on case-by-case basis by individuals with appropriate training.
- For appraisal of applications of higher risk agents (that is, biologicals or other medicines whose mode of action is novel or uncertain) must be defined by the nature of the agent, degree of novelty, its intended pharmacological target and its intended recipient, regulators should have access to additional opinion from independent, specialist experts with research and knowledge of their field.
- Special considerations should be given to agents for which the primary pharmacological action for the proposed therapeutic effect cannot be demonstrated in an animal.
- Reconsider whether dose calculation, beyond reliance on “No Observable Effect Level” (“NOEL”) or “No Observable Adverse Effect Level” (“NOAL”) in animal studies should be taken.
- Careful consideration should be given to the route and administration of the first dose in FIM trials with careful monitoring for an exaggerated response.
- New agents in FIM trials should be administered sequentially to all subjects with an appropriate period of observation between dosing.
- FIM studies of higher-risk medicines should always be conducted in an appropriate clinical environment supervised by staff with appropriate levels of training and expertise.
The CHMP has determined that, as far as calculation of first dose in man is concerned, for high-risk medicinal products, an additional approach be taken: Minimal Anticipated Biological Effect (“MABEL”). This comprises the anticipated dose level leading to minimal biological effect level in humans. To determine MABEL, all in vivo and in vitro data and information, derived from pharmadynamic/pharmacokinetic data, should be utilized and included in a modelling approach. Other safety factors should be applied in the calculation of MABEL:
- The novelty of active substance
- Its biological potency mode of action
- Degree of species specificity
- Shape of dose/response cure
When both NOEL and MABEL have been calculated, the lower dose should be administered in FIM trials.
So, the challenges in future FIM trials are recognized in potential higher-risk agents and the need to develop relevant potency assays for these agents. There is a requirement for a far greater sharing of information amongst all agencies which will create an administrative burden but also, it is hoped, a greater general understanding of novel modes of action. As far as the calculation of starting doses is concerned, it is clear that animal tests may not always provide an appropriate baseline, and as such, the design of trials will have to be amended. There is a drive towards risk reduction and risk management, but also accountability for taking those steps. We are likely to see further centers for excellence being developed to ensure that subjects have the highest quality of adequate support.
Sally Shorthose is an Intellectual Property and Life Sciences Partner for Bird & Bird, located in London, UK. Having qualified in 1988, Sally spent 11 years working in-house firstly as senior legal advisor at ICI/Zeneca and latterly as Legal Director of Novartis UK. Sally provides advice in relation to the protection and exploitation of a full range of IP rights and commercial advice, including licensing and exploitation agreements, research, development and marketing collaborations, as well as providing regulatory advice.
This article was printed in the May/June 2010 issue of Pharmaceutical Outsourcing, Volume 11, Issue 3. Copyright rests with the publisher. For more information about Pharmaceutical Outsourcing and to read similar articles, visit www.pharmoutsourcing.com and subscribe for free.