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NEWS: Susan Mayor Squeezing academic research into a commercial straitjacket BMJ 2004; 328: 1036 [Full text]

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You can have more than one sponsor

Kiain J.D. Balloch   (30 April 2004)

The EU Directive may prevent many useful clinical trials of modest proportions with minimal risk

Trevor LP Watts   (30 April 2004)

What is it about academics?

Malcolm VandenBurg   (3 May 2004)

EU directive is damaging.

Sue M Richards   (5 May 2004)

Do investigators know about the EU directive?

Moira MB Mungall, Eleanor Dinnett, Mary Fraser, Karen L. Bell, Lisa Macaulay, Caroline Connolly, Brian Rae, Allan Gaw   (12 May 2004)

NOT ALL BAD NEWS

Janet H Darbyshire   (5 June 2004)

You can have more than one sponsor 30 April 2004
Kiain J.D. Balloch, Health Effectiveness and Ethics of Research Officer Forth Valley NHS Board, Spittal St. Stirling, FK8 1DX Send response to journal: Re: You can have more than one sponsor	The new regulations relating to the EU Clinical Trials Directive do permit more than one sponsor per study. However for functions such as applying to NHS RECs, there has to be an agreement that only one of the named sponsors will perform that function. It is also common practice for pharmaceutical companies to use employ Contract Research Organisations to carry out many of the sponsor's functions during clinical trials. Form COREC's SOPs for NHS RECS: "Sponsor of a clinical trial The person who takes on ultimate responsibility for the initiation, management and financing (or arranging the financing) of a clinical trial. Note: The Regulations allow for two or more persons to take responsibility for the functions of the sponsor. Where this applies, they require that one of the sponsors should take responsibility for each of the following group of functions: (a) communications relating to substantial amendments, modified amendments and the conclusion of the trial (b) communications relating to urgent safety measures (c) pharmacovigilance reporting." Competing interests: None declared
The EU Directive may prevent many useful clinical trials of modest proportions with minimal risk 30 April 2004
Trevor LP Watts, Head of Department of Periodontology and Preventive Dentistry Guy's King's and St Thomas' Dental Institute, London SE1 9RT, UK Send response to journal: Re: The EU Directive may prevent many useful clinical trials of modest proportions with minimal risk	I research in periodontology, a dental specialty in which it is relatively common to set up a small trial to test treatments of medical or surgical nature, or both combined. Typically, such trials may involve 30 or so patients in a crossover (or the special dental version of a crossover – the split mouth) trial, or 50 upwards in a group comparison. Usually we are interested in clinical significance more than just statistical significance and Type 2 error is not a big issue, so numbers often do not need to be large. The number of investigators may vary from just 2 to perhaps 6 or more. The risks in these trials are usually no more than those of the treatments involved. Placebos are sometimes used when disease is reversible, or unlikely to progress further in the short timescale (a few months) of most of these studies. In the opinion of many investigators, including myself, there is often a significant risk in not undertaking a trial: namely, that optimal treatment will not be discovered, and that our patients will suffer as a result. With regard to randomization, I view specific allocation of the patient by the clinician to one treatment as immoral if it is not known by experiment to be better than the other. A patient always has the right to refuse participation in a trial, or to choose treatment if the best is not known. Participation in some periodontal trials may also benefit a patient’s future treatment, as we are usually treating chronic diseases which may recur. The EU Directive plainly has not considered the large number of small trials like these which benefit patients by providing better knowledge of treatments for common diseases. Normal authorization is in any case often a time-consuming procedure because both lay persons and medical colleagues on ethics committees are unfamiliar with the field. To add a bureaucracy designed by people unfamiliar with such trials (which may also occur in other parts of dentistry and some medical specialties) seems likely to kill a lot of good research and deprive patients of benefits. Competing interests: I have run or participated in a number of small trials of the type described. As a patient, I have had benefits from the findings of such trials.
What is it about academics? 3 May 2004
Malcolm VandenBurg, Private Medical Practitioner 114 Harley Street W1G 7JJ Send response to journal: Re: What is it about academics?	This is deja-vu. Twenty years ago the European Pharmaceutical Industry was pleading lack of resources and lack of need to bring good clinical practice into Europe. When I first started lecturing on good clinical practice,25 years ago, the response was WHY! We dont need it! We can not afford it! Doctors can be trusted! And then: WOW ! People began to realise that doctors are only human, even if they are proffesional Gerneral Practitioners. Even Hospital Consultants and the odd Proffesor will for many reasons (not only financial) be careless at best and cheat at worst. In the United States the FDA and NIH have insisted on a standard similar to good clinical practice for 30 years although it was not called that by the FDA untill the last 10. The FDA has caught many US and European investigators out, the NIH many American. It is not only in Pharmaceutical research where the doctor is fraudulent. The literature abounds with similar instances in "pure" academic research. I have had the misfortune to be asked to review two such cases involved in PhD's although confidentiality prevents me in naming names. The priciples of the clinical trials directive are simple. 1) Protection of the human subject. 2) Ensuring the validity of the data. Who can argue against either. Someone must take the responsibility for ensuring both, a committee can not. Thus the need for a sponsor. For the first we must have informed consent and ethics approval. Who would argue with that? Doctors do cheat. Doctors will put patients into trials without any (yet alone fully)informed consent. Someone has to check each and every consent form. A UK Unuversity failed an FDA audit as most consent forms could not be found. Adverse events must be fully documented and investigated to protect future subjects and allow informed consent. The trial supplies MUST be manufacture, distributed and stored according to Good Practices or patients will suffer. There is not one requirement of the directive that is unessecary. For the second it is a sad fact of life that medicine has within it people covering the whole spectrum of morality. Why should they be a super selected perfect sample. They will cheat for many reasons. Some financial.Some academic. Some to do with reputation. Some to prove there hypothesis. Some for no good reason other than there personality. Source document verification and complete monitoring is expensive, yet it is an imperative in these imperfect times. It is time for the academics to stop whinging and do what is nessecary in their patients and their future patients best interests. That is to find the money and perform the studies to an acceptable level compliant with the European Clinical Trials Directive. Competing interests: I am a Pharmaceutical Physician who has written many books and articles on Good Clinical Practice and trained the Pharmaceutical Industry and Investigators world wide. Ihave recently written on the imposiblity of True Research Governance in the NHS and the lack of desire of academic research in the UK to folow the priciples of the Clinicasl Trials Directive.
EU directive is damaging. 5 May 2004
Sue M Richards, Cancer Research UK staff scientist CTSU, Oxford University, OX2 6HE Send response to journal: Re: EU directive is damaging.	There is no doubt that the EU Directive will be damaging to clinical research, and hence to patients. Noone would dispute its aims to 1) Protect the human subject, and 2) Ensure the validity of the data, but many recognise that it will not achieve this. Pharmaceutical industry trials are ultimately for the purpose of improving profits, whereas publicly run trials aim to improve the outcome for patients. It is difficult and time-consuming to explain to those not involved in trials the exact nature of all the problems caused by the implementation of the directive, but using the same bureaucratic system for both is like using a sledge hammer to crack a nut, many nuts will not be intact at the end of the process. It would be much better to use a well-designed nut-cracker. Competing interests: Statistician and trial manager working on publicly funded leukaemia trials.
Do investigators know about the EU directive? 12 May 2004
Moira MB Mungall, Clinical Research Fellow Clinical Trials Unit, 4th Floor Walton Building, Glasgow Royal Infirmary, Glasgow G4 0SF, Eleanor Dinnett, Mary Fraser, Karen L. Bell, Lisa Macaulay, Caroline Connolly, Brian Rae, Allan Gaw Send response to journal: Re: Do investigators know about the EU directive?	Editor, The article by Mayor (1) describes how the new EU Clinical trials regulations threaten academic research by creating onerous sponsorship responsibilities, but little has been said about the responsibilities of investigators and the concerns these raise. The European Union Clinical Trials Directive (EUCTD) was published in 2001(2), but it has only recently come to the attention of the wider medical community. We have evaluated awareness of the EUCTD, and more specifically, awareness of Good Clinical Practice (GCP) since the latter is an essential element of directive compliance. We sent a questionnaire to 2816 researchers in 5 NHS Trusts in central Scotland earlier this year. The sample group represented all potentially active researchers known to the Trusts’ Research and Development departments and included those with clinical or administrative roles. The clinical group represented a mixture of primary and secondary care providers plus academics and non-academics. We received 646 completed or partially completed surveys, 454 from GPs or other doctors. The overall response rate was only 23%, however, it is likely that responders were particularly interested in research so the results will potentially overestimate the amount of knowledge of the entire group. A total of 357 respondents (55% of the total) said that they had been involved in clinical trials over the past 3 years. Within this group were 228 doctors who completed the remainder of the questionnaire. Only 79 doctors (35%) had heard of the EU directive. 106 doctors(46%) had received some training in GCP but 49 of them (46%) had trained more than 3 years ago. Of the 224 doctors who chose a definition for GCP just 131 (58%) chose the correct one. Although this is a small group it raises concerns about the level of knowledge about the requirements of the EUCTD. The Medicines for Human Use (Clinical Trials) Regulations (3) charge the sponsor with ensuring ‘ the conditions and practices of good clinical practice are satisfied or adhered to’. If only half of investigators are familiar with GCP then sponsors face a significant challenge with regard to training. Educational programmes do exist but many are aimed at pharmaceutical companies and are prohibitively expensive for an independent investigator contemplating non- commercial research. What is required is for health boards or universities to provide readily accessible educational programmes that will allow doctors in the United Kingdom to continue to conduct high quality non- commercial clinical trials while fulfilling their legal responsibilities. References 1. Mayor S. Squeezing academic research into a commercial straight jacket. BMJ 2004; 328: 1036 2. Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. Official J Eur Communities 2001;L121:34-44. 3. Statutory Instrument 2004 No. 1031 The Medicines for Human Use (Clinical Trials) Regulations 2004. http://www.hmso.gov.uk/si/si2004/20041031.htm (accessed April 21, 2004) Competing interests: MMBM and AG provide educational courses on Good Clinical Practice including the implications of the EU Clinical Trials Directive
NOT ALL BAD NEWS 5 June 2004
Janet H Darbyshire, Chairman of MRC/DH joint project Steering group Director, MRC CTU, 222 Euston Road, NW1 2DA Send response to journal: Re: NOT ALL BAD NEWS	Susan Mayor’s article “Squeezing academic research into a commercial straitjacket” (BMJ 2004; 328: 1036 (1 May) highlighted the academic community’s significant concerns about the EU Clinical Trials Directive. It is a pity that she buried the good news . The article referred to the Medical Research Council's May 2003 impact assessment of the draft UK regulations. Much has changed since then. The UK Medicines for Human Use (Clinical Trials) Regulations, which came into force on 1 May, contain significant improvements over the draft regulations. In particular, it is the principles of the International Conference on Harmonisation Good Clinical Practice that will be the GCP standard for the UK. The MHRA now recognises that there many kinds of clinical trial and that the controls need to appropriate and proportionate to the trial. The full detailed guidelines that accompanied the ICH GCP are likely to be appropriate only to a small fraction of academic trials, specifically those designed to gain marketing authorisation. The regulations’ provision for a group to accept the sponsorship responsibilities recognises that many trials do not fit within the “single sponsor” model. How this might work is set out in the papers published by the MRC/DH Joint Project to Codify Best Practice in Publicly Funded Trials. The Joint Project aims to cover a range of topics from sponsorship and insurance, clinical trial commencement, risk assessment, trials supplies and safety reporting (http://www.ncchta.org/eudirective/index.asp). It provides information of practical value to trialists and R&D managers. As the BMJ points out and the Steering Group of the Joint Project recognises, some important problems remain to be resolved – not least how sponsorship and insurance arrangements will be handled in multinational European trials. It is time to stop shooting at old targets. We need intelligent collaboration to tackle the real issues. Professor Janet Darbyshire Chairman, MRC/DH Joint project Steering Group Competing interests: None declared