Trials Data - Part I: Offences under the MHU Regulations 2004

By Matthew Holford

Ed: Here Matthew continues his rants with an in-depth look into the transparency of the Medicines Healthcare and products Regulatory Agency (MHRA)

Matthew writes exclusively for Seroxat Sufferers.

I was moved to ask the MHRA a month or two back about the investigation that its Intelligence Unit (note: not the police) is conducting into allegations that GSK withheld trials data concerning its Seroxat paediatric trials. If my memory serves me, the investigation began some 3-4 years ago, and I must say that I'm impressed that the MHRA should be so diligent in its efforts, given that, whilst it is a criminal offence to withhold trials data, the penalty is a maximum term of imprisonment, upon conviction, of only two years and/or a maximum fine of £50,000, if I remember aright (but more of that, later). Presumably it wants to ensure that it has an absolutely watertight case to present to the CPS (or is that the Department of Health?) for a decision on whether or not to prosecute, should it come to that.

Anyway, I thought it would be a valuable exercize to understand the legislation that the MHRA is implementing in its investigation. It wouldn't disclose any details to me, on the ground that it might prejudice any subsequent prosecution, and rightly so. As such, I'm limited to deconstructing The Medicines for Human Use (Clinical Trials) Regulations 2004 (as amended by the Medicines for Human Use (Clinical Trials) Amendment Regulations 2006) which governs this area of healthcare regulation.

To be honest, I wasn't really sure how I should approach this, and I decided to fall back on the format presented to me by my alma mater, Birkbeck College School of Law. To this end, I'm going to present you with the offences, first, then the defences, and finally the sanctions. Any extraneous bits and bobs, like a discussion of the role of the relevant Ethics Committee, I'll tack on at the end.

Offences

Regulation 12(1) - It is an offence to start, cause to be started, or conduct a clinical trial, without the requisite approval of the Ethics Committee and the licensing of said trial by the regulatory authority (ie, the MHRA).

Regulation 12(2) - It is an offence to recruit patients or to advertise for patients to take part in a trial, without the requisite approval of the Ethics Committee and the licensing of the trial by the MHRA.

Regulation 13(1) - It is an offence to sell an investigational medical product for the purpose of administering said product in a clinical trial unless the trial has been authorized by the MHRA or, where the product has been manufactured within the EU, but outside the UK, the product is compliant with the Clinical Trials Directive (2001/20/EC)

Regulation 27 - It is an offence to not inform the MHRA in writing of the termination of a trial within 90 days of said termination. However, if the trial is terminated early (ie, before the date or event specified in the protocol has occurred), then the sponsor must inform the MHRA within 15 days of said termination.

Regulation 28(1) to (3) - It is an offence to not conduct a trial in accordance with good clinical practice, whatever that might be. It is an offence to not put in place arrangements to ensure that good clinical practice is adhered to. It is also an offence to charge participants in a trial for the products being trialled, subject to certain restrictions under the National Health Service Act 1977 (and the corresponding legislation pertaining to Scotland and Northern Ireland).

Regulation 29 - It is an offence to conduct a trial other than as specified in the particulars of the documentation requesting authorization of that trial, other than where urgent safety measures need to be taken.

Regulation 29A - This Regulation was introduced under the 2006 Amendment Regulations and provides that where there is a serious breach (ie, a breach which impacts upon the safety of the trialists, or undermines the scientific value of the trial) of the protocol governing the trial, or where the principles and conditions of good clinical practice have been breached, then there is a duty to inform the MHRA within 7 days of such breach coming to light. It is a criminal offence to fail to do so.

Regulation 30 (2) - Where urgent safety measures have been implemented, it is an offence to fail to report immediately (within 3 days) in writing this deviation from the conduct of the trial, as originally communicated in the documentation, to the MHRA and the Ethics Committee.

Regulation 32(1),(3) and (5) to (9) - It is an offence for an investigator to fail to report a serious adverse event (SAE) to the sponsor immediately (presumably within 3 days, but it doesn't state a timescale). It is an offence for the investigator to fail to make a detailed written report of the event, following the immediate report to the sponsor. I'm not sure what sub para (5) adds, aside from the fact that it indicates that reporting requirements for adverse events should be set down in the protocol, particularly those that impact upon the very safety of the trial, as I read it. Sub paras (6) to (8) identify particulars of the information which must be kept and supplied, failure to do so being an offence. Finally, under (9), it is an offence for the sponsor to keep detailed records of all adverse events reported to it by investigators.

Regulation 33(1) to (5) - It is an offence for the sponsor of a trial to fail to record and report as soon as possible (ie, within 7 days) to the MHRA (or relevant authorities, if the trial is being conducted outside the UK) and to the Ethics Committee concerning a suspected unexpected(?) SAE, which is fatal or life-threatening (the time limit is 15 days, if the SAE is non-fata/life threatening). If any additional evidence is available, then it is an offence to fail to make this available to the MHRA within 8 days of the initial report having been submitted. The duties outlined above may be discharged by entering the report on the European database (established under Art 11 of the Directive) - let's just assume that that's being monitored, for the time being, shall we? Finally, under (5) it is an offence to fail to disclose to investigators in a trial a SAE that occurs in a different trial, but which uses the same products.

As an aside, I see that under 33(6) there is a duty on the regulator to ensure that any reports made under Regulation 33 are included on the European database. However, if a sponsor has reported direct to the database, then unless the MHRA is monitoring the database, it won't know if new information has been entered, unless there is a duty on the sponsor to advise the MHRA of any new entries, (I saw no mention of such a duty, in the Regulations). Indeed, the duty to enter details of SAEs on the database, as it pertains to the MHRA, is limited to those brought to its attention. I spy with my little eye a loophole.

Regulation 34 - Where a trial is being held in several sites, presumably including sites outside the EU, in addition to a site(s) in the UK, then reports of SAEs must still be made to the European database. It will be an offence for the sponsor to fail to do so.

Regulation 35(1) - It is an offence for a sponsor to fail to report, at the end of each reporting year (whenever that may be), a list of all SAEs identified during trials conducted, including SAEs experienced by placebo trialists. This list should include trials in the UK and elsewhere, and a safety report should also be submitted for any triallists affected.

Regulation 36(1) - It is an offence to assemble, manufacture or import an investigational medicinal product other than in accordance with the manufacturing authorization that has been granted. However, under Regulation 37 where a trial, etc, is being carried out in a hospital or health centre, this restriction does not apply.

Regulation 42 - It is an offence to not comply with certain specified manufacturing standards.

Regulation 43(1) and (6) - It is an offence for a manufacturing authorization holder to fail to have a "qualified person" at its disposal to carry out the duties specified under Arts 13(3) and (4) of the Directive.

Regulation 49 - There's a bunch of offences relating to the above, and to labelling, including possession of medicinal products with an intention to sell, in contravention of 13(1), labelling of products other than in accordance with Regulation 46, and so on.

Regulation 50 - There is a range of offences under Regulation 50, pertaining to the provision of false or misleading information. I quite like the look of Regulation 50(2), which provides that anybody who provides the MHRA or the Ethics Committee with "relevant information," which is false or misleading in any material particular, will have committed an offence. Relevant information will be information relating to the evaluation of safety, efficacy and quality of a product; or the safety or scientific validity of a trial; or whether the principles of good clinical practice are being adhered to.

Comment

This is a technical and quite wide-ranging piece of legislation. It should be remembered at all times that this legislation came into force on 1 May, 2004, and that no legislation will be retrospective. That is to say, if a person does something that one does not like, one should not formulate a rule forbidding that conduct, and then punish the person for having done what they did - the rule with only have effect with respect to similar conduct, in the future.

So, back in 1998, when SKB was dicking around with the 329 data, there was presumably no specific offence relating to the failure to submit information concerning SAEs, as there is now. However, if one were to withhold data completely legitimately, perhaps on the ground that it was proprietary information (this is customary in the pharmaceutical industry, I understand), and then a piece of legislation came into effect that provided that one had to give up that information, then if one continued to withhold it, that would constitute an offence. That withholding data in 1998 may have amounted to an offence in force at that time is another matter.

It would appear that there is a duty, under Regulation 34, for SAEs to be notified on the European database, even though they occurred in, say, the US. Assuming that Seroxat was also trialled in the UK, which appears to be a pre-requisite, it might be amusing to trawl the database, in an idle moment!

It seems that raw data is still regarded as propietary information. As such, even though the MHRA would be well within its remit to demand sight of raw data, during the course of its assessment process, there is no obligation upon the sponsor to submit this sort of information of its own accord (although there is an obligation to not supply false or misleading information). Indeed, given the Select Committee's comments, it seems that the MHRA tends not to bother with this kind of thing, and I'm not even sure that, in practice, individual assessors may demand that sort of information - they can ask the MHRA to ask the sponsor, but that's all, I think.

If the MHRA did require a copy of all raw data to be made available as a standard feature of the marketing authorization portfolio, it would be able to scrutinize these up front, and any discrepancies in interpretation could be ironed out, right then and there. God forbid that such a massive grey area should be removed from discussion, though. As such, even with the 2004 Regulations (as amended) in place, it is not beyond the bounds of the imagination to conceive a scenario where a sponsor withholds certain information, or summarizes it in its own favour, and then pleads that a particular SAE only became apparent, once the drug had been on the market, for a while. Only an investigation and subsequent prosecution would demonstrate whether or not this has been done, because any evidence of prior knowledge of a risk will be held by the marketing authorization holder.

Anyway, I think I've reached saturation point with this not-very-interesting piece of legislation for the time being, so I'll leave the gentle reader to digest that, and I will address the question of defences, in due course. To be honest, I doubt that there's very much precedent in this area, not least because the legislation has not been around for very long. Because of this, I think it boils down to a matter of expert opinion as to whether one were successful in obtaining a prosecution, but I'll explain why I think that, next time!

Matthew Holford (c) 2007

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