Policy responses and statements
- Name of organisation:
- Department of Health
- Name of policy document:
- Expert Scientific Group on phase one clinical trials - A consultation
- Deadline for response:
- 14 September 2006
Background: This interim report is published by the Expert Scientific Group (ESG) brought together to examine the design of phase 1 clinical studies. The Expert Scientific Group was convened by the Secretary of State for Health to look at how to improve the safety of drug trials involving products such as monoclonal antibodies, following adverse reactions experienced by participants in the clinical trial of the drug known as TGN1412 earlier this year.
The ESG was asked to make an interim report in 3 months and to seek stakeholder opinions in formulating its recommendations. This interim report summarises the ESG's conclusions so far. Some results from experiments recommended by the ESG to clarify the toxicity seen in the TGN1412 trial are awaited for independent tests carried out by the National Institute of Biological Standards and Control. These results will be evaluated and discussed in the ESG's final report later this year. The final report will also take account of further stakeholder opinions and comments received after the submission of this interim report.
COMMENTS ON
DEPARTMENT OF HEALTH EXPERT
SCIENTIFIC GROUP ON PHASE ONE
CLINICAL TRIALS - A CONSULTATION
The Royal College of Physicians of Edinburgh is pleased to respond to the Department of Health on Expert Scientific Group on phase one clinical trials - A consultation.
General comments:
The TGN1412 trial was a disaster for the individuals concerned but also a severe setback for confidence in the drug development process so this rapid response should be widely welcomed. As recognized in the report, the first human exposure to a new medicine will always carry some risk but the events earlier this year suggested that those risks were not being minimized. Over-regulation is a scourge of modern science but change in this area is required.
This is a very useful interim report, which will provide greater safety for subjects (patients and healthy volunteers) taking part in Phase 1 trials (particularly first-in-man studies, where the greatest risks lie). It produces no major surprises and many of the points made were mooted in the medical journals shortly after the catastrophe occurred.
The Expert Scientific Group (ESG) is described as an independent committee established by the Secretary of State for Health. It would be useful to know how members of the group were selected, what were the criteria for selection (e.g. how many have experience of Phase 1 trials) and lastly, what is the basis of the independence. Many members of the group serve on government committees and these should be described.
It is helpful that the ESG has identified a series of potentially high risk new medicines, because for standard small molecule drugs, of the sort that have been studied in Phase 1 trials over the past 30 years or more, the risks of unexpected or devastating adverse effects as seen with TGN1412 have not been a feature, and standard pre-clinical studies have served us well in predicting the doses that should be given to man, and the range of likely side effects in phase I studies.
We would strongly support efforts to share SUSARS between regulators in Phase 1 studies worldwide. However this may prove hard to implement, because the pharmaceutical industry likes a high degree of secrecy, and may invoke issues of competition. However, the pharmaceutical industry is a global business and it is inappropriate to expect a patient to take a risk, say, in the UK with a drug for which a risk could have been predicted if the knowledge of regulators with drugs of the same class from a competitor company was available from the US or Japan. The additional levels of safety (lowest dose possible, sequential dosing, etc.) all seem very sensible for these high risk drugs.
We support the development of a limited number of specialist centres around the UK to support such studies, which need tertiary hospital skills in caring for subjects adversely affected by the treatment.
One issue that is not raised in the report, and not within the ESG’s remit, is trial subject compensation. However, this issue is worth raising. In particular, there are reasons to think that compensation arrangements could be improved for subjects in Phase 1 studies, and even if they are not improved volunteers should be clear of what compensation arrangements have been made. This is currently far from transparent.
We support the major recommendations that
- All the investigators involved should be fully trained
- High risk drugs should be identified
- Use of an alternative initial dose-setting assessment for certain novel agents
- Giving only one subject the active medicine on the first day
- Following this with `staggered dosing' as doses are increased
- Conducting high risk studies at a hospital with intensive care facilities
Chapter 1 - Executive Summary
Background
The group describes making recommendations to increase the safety of “similar trials”. This suggests that they wish to increase the safety of other trials on which there are serious adverse reactions. Is this implication deliberate?. We would rather assume that the group was set up to increase the safety of Phase I trials of novel compounds.
Summary recommendations
Recommendation 1. The strategy for preclinical development of a new medicine and the experimental approaches used to assemble information relevant to the safety of phase one trials must be regarded as science-based decisions, made and justified case-by-case by investigators with appropriate training.
Agreed
Recommendation 2. Developers of medicines, research funding bodies and regulatory authorities should expedite the collection of information on unpublished preclinical studies and phase one trials, and explore the feasibility of open access to this database.
Agreed, but will sensitive information really be made open - is this realistic?
Recommendation 3. Regulatory authorities should consider ways to expedite the sharing between regulators worldwide of information on Suspected Unexpected Serious Adverse reactions (SUSARs) in phase one trials, and explore the feasibility of open access to this data.
In general this is strongly supported and should be achievable but surely information should be collected on all suspected serious adverse reactions, not only when they are unexpected. The term “unexpected” is a difficult one anyway but there is really no reason to include it in this situation.
Recommendation 4. A broader approach to dose calculation, beyond reliance on 'No Effect Level' or 'No Adverse Effect Level' in animal studies, should be taken. The calculation of starting dose should utilise all relevant information. Factors to be taken into account include the novelty of the agent and its mechanism of action, the degree of species-specificity of the agent, the dose-response curves of biological effects in human and animal cells, dose-response data from in vivo animal studies where relevance to human has been validated, the calculation of receptor occupancy versus concentration and the calculated exposure of targets or target cells in humans in vivo. The 'MABEL' approach is a good option for achieving this.
This makes sense but might not avoid allergic-type reactions. It would be helpful to explain what the MABEL means at this point.
Recommendation 5. If different methods give different estimates of a safe dose in humans, the lowest value should be taken as the starting point in first-in-man trials and a margin of safety introduced.
Yes – obviously.
Recommendation 6. When it is likely that preclinical information, for any reason, may be a poor guide to human responses in vivo, the starting dose in first-in-man trials should be calculated to err on the side of caution.
It is not necessary to use the words “to err”. The starting dose in first-in-man trials should be at a value compatible with safety.
Recommendation 7. Careful consideration should be given to the route and the rate of administration of the first dose in first-in-man trials, with careful monitoring for an exaggerated response.
This should be expanded to say that giving drugs intravenously to humans carries a higher degree of risk than giving the drug orally. Several stakeholders mentioned this and in fact the ABPI/BIA recommendations included a note to say the drug should be given over a one hour infusion if given intravenously.
Recommendation 8. Decisions on starting dose and dose escalation should be made on a case-by-case basis, and should be scientifically justifiable, taking account of all relevant information
This should include a note to say that dose escalation should not occur until all data from the previous dose have been reviewed.
Recommendation 9. The decision whether to conduct a first-in-man trial in healthy volunteers or in volunteer patients should be carefully considered and fully justified, taking into account all factors relevant to the safety of the subjects and the value of the scientific information that is likely to be obtained.
This really makes no point whatsoever. Of course the decision to conduct a trial on healthy volunteers should be “considered carefully and fully justified”. No one would doubt this statement. What the committee means to say is that some drugs should not be given to volunteers because the information likely to be available from these studies does not justify the risk to the volunteer.
Recommendation 10. Principal Investigators in first-in-man trials should always be appropriately qualified and satisfy themselves that they know enough about the agent, its target and mechanism of action to be in a position to make informed clinical judgements.
Saying that principal investigators should be appropriately qualified is not very specific. What are appropriate qualifications?
Recommendation 11. In first-in-man studies where there is a predictable risk of certain types of severe adverse reaction, a treatment strategy should be considered beforehand. This should include the availability of specific antidotes where they exist and a clear plan of supportive treatment including the pre-arranged contingency availability of ITU facilities.
Availability of ITU facilities is a KEY safety recommendation but defining high risk is difficult. Will the participants be told that they are in a high risk study?In two of the stakeholder presentations the statement is made that for some compounds, volunteer studies should be conducted only in a Phase I clinic attached to a hospital.
Recommendation 12. First-in-man studies of higher risk medicines should always be conducted in an appropriate clinical environment supervised by staff with appropriate levels of training and expertise with immediate access to facilities for the treatment and stabilisation of individuals in an acute emergency and with pre-arranged contingency availability of ITU facilities.
One could debate whether “higher risk medicines” should ever be given to volunteers.
Recommendation 13. New agents in first-in-man trials should be administered sequentially to subjects with an appropriate period of observation between dosing.
This is an important recommendation that would have prevented many of the problems with the recent study. Two stakeholders recommend that a leading dose design should be used in Phase I protocols i.e. only one person should receive the active compound on the first day and only one person should receive the larger dose on subsequent dosing measurements. This would take account of recommendations 14 and 15 also.
Recommendation 14. The interval of observation between sequential dosing of the subjects should be related to the kind of adverse reactions that might be anticipated based on the nature of the agent, its target and the recipient.
Agree - follows from above
Recommendation 15. A similar period of monitoring should occur between sequential dosing of subjects during dose escalation.
Agree - follows from above
Recommendation 16. More communication should be encouraged between developers and the regulator at an earlier stage before an application is filed, especially for higher risk agents, to ensure that there is time for an appropriate consideration of any safety concerns without introducing undue delay to product development. Ways to increase communication between the regulator and research ethics committees should also be considered.
It is not clear how the research ethics committees can contribute to safety at this point. Perhaps they should not even be considered with regard to safety but only with the ethics. It is important that the ethics committee can be reassured that the data have been reviewed by appropriate experts and declared safe. Perhaps that is what the recommendation means when it is asks for better communications between developers and regulators. In this respect there may be an opportunity for special considerations of safety at a more central level through the implementation of the Report of the ASd Hoc Committee (of the NPSA) on the Operation of NHS Research Committees (August 2006)
Recommendations 17. For appraisal of applications for trials of higher risk agents, as defined by the nature of the agent, its degree of novelty, its intended pharmacological target, and its intended recipient, the regulator should have access to additional opinion from independent, specialist experts with research knowledge of their fields.
Agreed
Recommendation 18. An Expert Advisory Group (EAG) of the Commission on Human Medicines, or a similar body, might undertake this role with a core membership of appropriate experts and the ability to co-opt additional experts as the need dictates.
Agreed. However although external peer review is always useful it is not clear who the appropriate experts will be
Recommendation 19. Consideration should be given to introducing some flexibility in the time-scale of clinical trial appraisal in exceptional cases of unusual complexity.
It is not clear how flexibility in the timescale will increase safety and it may be more difficult specifically to identify these situations in any case
Recommendation 20. The availability of 'hands-on' experience in the planning and conduct of clinical trials should be widened, for example by secondment periods to commercial organisations within postgraduate training programmes, or the development of specialist centres within the NHS and Universities
Agreed.
Recommendation 21. The feasibility of developing specialist centres for phase one clinical trials of higher risk agents and advanced medicinal products should be explored.
This should be supported.
Recommendation 22. The regulatory process for first-in-man trials of higher risk agents and advanced medicinal products based on innovative technologies should be subject to frequent review.
Agreed
Additional Comments
The fundamental questions to be asked following the trial of TGN1412 at Parexel are as follows:
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Should healthy volunteers be given a drug such as this? There are many real doubts about whether there is any benefit in giving a drug such as this to healthy volunteers. Because it is given intravenously there is very little to be learned with regards to pharmacokinetics.
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What is the correct dose for a study of this nature? Even in retrospect this is difficult to establish but it is known that animal studies are probably not predictive of human dosage and toxicity for a drug of this nature.
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How should the study be conducted? There seems little doubt that the drug should not be given to six volunteers on one day as a first exposure to humans. At least two of the stakeholders recommend a leading dose design of the protocol in which only human receives the test drug on the first day. If given intravenously the dose should be administered over a considerable period of time to allow any adverse events to be apparent before the end of dosing.
These three points should be highlighted in the executive summary and in the conclusion of the expert group.
Chapter 3 – Pre-clinical development of TGN1412
Chapter 4 – Transition to Clinical Development of TGN1412
Chapter 5 – Phase One Clinical Trial and adverse events at Northwick Park Hospital
Chapter 6 – MHRA GCP, GMP and GLP Investigations
Chapter 7 – Summary of Stakeholder Consultations
Chapters 3, 4, 5, 6 and 7 are largely factual and we have no specific comments to make on them.
Chapter 8 – Predicting Hazards in Preclinical to Clinical Transition
Background
In paragraph 1 it is important to make it clear that local research ethics committees cannot be responsible for deciding the safety of the study. The committee needs to be reassured that the data have been reviewed by appropriate experts and declared safe. As Dr Gennery points out in his presentation “someone needs to take responsibility for this in both the client company and CRO”. The committee needs to be reassured that these signatures are genuine and relate to appropriate senior staff.
Inherent Hazards of Certain Types of New Medicines
In general we agree with the inherent hazards of novel agents and it is right that they should be highlighted. It is not a surprise that animal models are not predictive of human toxicity for the molecules described.
Chapter 9 – Risk Reduction and Risk Management
In general, it is not appropriate to talk about first-in-man trials in volunteers with “higher risk agents”. If we can describe these agents as higher risk they should probably not be given to volunteers. The ESG should highlight that there is value in discussion between the preclinical expert and the clinical expert at the time of first administration to man. This may be more important than regulatory interaction.
Sharing of information
We agree that information should be available but it has been collected for some years in the United Kingdom (at least for CROs). We suggest that all suspected serious adverse reactions should be reported to the regulators and not just unexpected serious adverse reactions.
Transition from preclinical to clinical development
We agree with the recommendations about starting dose. In any event there must be a serious scientific justification for the dose selected and not just a fraction of the no adverse effect dose. We believe it is always ethical to study a dose that is ineffective particularly when volunteers are involved. If only effective doses are studied then toxicity is probably inevitable and a dose response relationship, if one exists, is difficult to establish.
Clinical
Choice of subjects for Phase One Trials
Recommendation 8 is really not very helpful. The decision whether to conduct a first-in-man trial in volunteers or patients is obviously going to be carefully considered. It would be useful to have a few more comments around this guideline. If the drug needs to be given intravenously, one should be very sure what information is going to be obtained in volunteers that could not be obtained in patients.
Clinical Environment of Phase One Trials
The group should be clear about what is an appropriate qualification for a Principal Investigator who will undertake and supervise a trial. There is much repetition in the section about supportive treatment and ITU facilities. In fact recommendations 10 and 11 are almost identical.
Sequential Dosing of Trial Subjects
This is one of the most important aspects of this report. It is obvious that we should not support first administration studies in which six volunteers are given the drug on the same day intravenously. A leading dose study in which only one volunteer or patient receives the active drug or escalated dose is obviously the way to proceed. This proposal is made in at least two of the stakeholders’ presentations.
Regulatory
The regulators need to be satisfied that the data have been reviewed by appropriate experts and that safety has been considered when designing the dosage regimen and protocol. There are many ways to do this but simple regulatory interaction will not do it on its own. Appropriate experts need to be consulted.
Skills and training
There is no doubt that there needs to be approved training in the conduct of Phase I studies. However the teaching of pharmacology and clinical pharmacology in medical schools has reduced and it will not be easy to find doctors with appropriate expertise in Phase I trials in the future in the United Kingdom.
Copies of this response are available from:
Lesley Lockhart,
Royal College of Physicians of Edinburgh,
9 Queen Street,
Edinburgh,
EH2 1JQ.
Tel: 0131 225 7324 ext 608
Fax: 0131 220 3939
[11 September 2006] |
