Difficulty in acquiring clinical trial authorisations from ethics committees for

Their complex nature means that some ATMPs being developed encounter further difficulty in acquiring ethical approvals for clinical trials. Article 6.1.4 of the Clinical Trials Regulation requires the reporting Member State to submit via the EU portal, the final Part I of the assessment report, including its conclusion, to the sponsor and to the other Member States concerned within 45 days from the validation date. The conclusion shall be one of the following in view of the requirements set out in the Clinical Trial Regulation: (a) the conduct of the clinical trial is acceptable; (b) the conduct of the

672European Medicines Agency. Concept paper on the revision of the ‘Guideline on 4 strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products’

(EMEA/CHMP/SWP/28367/07) Available at:

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/07/WC500210825.pd f. Accessed 28 July 2016.

673 In such trial a single dose of the investigational drug is given to each volunteer in a small group of clinical trial participants to assess the safety. Thereafter, if that is acceptable each participant in the next group receives a single dose at the next higher dose of the investigational drug. See European Medicines Agency, op.cit. for further details.

674 Op.,cit. 2.

675 In multiple ascending dose trials, each subject is treated on many occasions at a given dose level. The treatment is then increased progressively to higher doses in successive groups of volunteers if the safety and tolerability at the previous dose is acceptable. European Medicines Agency. op.cit. for further details.

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clinical trial is acceptable, but subject to compliance with specific conditions which shall be specifically listed in the conclusion; or (c) the conduct of the clinical trial is not acceptable. In case of clinical trial applications regarding IMP ATMPs, the assessment timeframe may be extented by further 50 days.

Yet, the possibly (and also likely) longer time frame is a minor problem in relation to some significant tensions (or even a risk of litigation) that may also arise in situations where there authorisation for a clinical trial has not been applied for (or granted) and physicians end up providing “experimental treatments” for patients instead.

For instance, in Finland physicians of a private hospital that used oncolytic viruses in experimental treatments “as a last resort” for single patients having different diagnosis of cancer and no option for conventional therapies were prosecuted for conduct of clinical trials without an authorisation to conduct a clinical trial. Such tailor-made, personalised treatments had been offered individually in a private hospital under the responsibility of a treating physician. The District Court of Helsinki found however, that despite experimental treatments generating new scientific data that had been published they cannot be perceived as clinical trials that require a clinical trial authorisation pursuant to Finnish Act on Medical Research.⁶⁷⁶

Despite this, it may appear obvious from an ethical perspective that therapeutic procedures that are not validated by clinical data should not be permitted; there may be acceptable reasons to allow the application of unproven treatments under certain specific conditions.⁶⁷⁷ In medical ethics and medical law, those procedures have been called “therapeutic experimentation” or a “therapeutic attempt”.⁶⁷⁸ Under the Declaration of Helsinki such attempts are regulated as a combination of research and care as well as treatments where proven interventions do not exist:

“[t]he physician may combine medical research with medical care only to the extent that the research is justified by its potential preventive, diagnostic or therapeutic value and if the physician has good reason to believe that participation in the research study will not adversely affect the health of patients who serve as research subjects.”⁶⁷⁹

As for unproven interventions, it is stated in the Declaration of Helsinki that:

[i]n the treatment of an individual patient, where proven interventions do not exist or other known interventions have been ineffective, the physician, after seeking expert advice, with informed consent from the patient or a legally authorised representative, may use an unproven intervention if in the physician's judgment it offers hope of saving life, re-establishing health or alleviating suffering. This intervention should subsequently be made the object of research, designed to evaluate its safety and efficacy. In all cases, new information must be recorded and, where appropriate, made publicly available.⁶⁸⁰

676 Ruling of District Court of Helsinki, Case R 13/8233, dated 2 October 2014.

677 See e.g. Fuchs, supra note 107, 143.

678 Ibid.

679 World Medical Association. Declaration of Helsinki - Ethical Principles for Medical Research

Involving Human Subjects, Article 14. Available at:

http://www.wma.net/en/30publications/10policies/b3/. Accessed 21 January 2016.

680 Op.cit., Article 37.

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It should be noted that “experimental treatments” under Declaration of Helsinki are not exempt from the EU-wide GMP standards on quality. Despite those therapeutic attempts being justified in specific circumstances, it is very important to carefully consider individual cases, and especially the patient’s ability to give informed consent to any such unapproved intervention.⁶⁸¹ The more unconventional a treatment is the higher the requirement is for physician to inform the patient about any potential risks involved with such an unapproved intervention. It would be highly undesirable if an unnecessarily high threshold to grant authorisations for clinical trials on ATMPs resulted in a situation where physicians end up proving experimental treatments instead of conducting systematic, controlled clinical trials. Since there is a need for more systematic assessment of the safety and efficacy of a product, data gained from experimental treatments cannot replace clinical trials. Therefore, national competent authorities should be vested with adequate knowledge on ATMPs to conduct risk-assessments of particular products and to be able to realistically assess risk-benefit balance of these products and sufficiency of quality system and risk management measures needed to eliminate or mitigate risks associated with clinical trials.

In addition, despite the EU-wide attempts to facilitate the administrative burden of clinical trials in multiple jurisdictions, it should be noted that the ethical assessment of clinical trials still remains within the competence of the national competent authorities of the Member States. Hence, the opportunity to conduct some types of research may differ from one jurisdiction to another. Ethical considerations that complicate the conduct of research range from access to primary materials to risk and safety related considerations of trials. Recital 18 of the Clinical Trials Regulation specifies that

“[i]t should be left to the Member State concerned to determine the appropriate body or bodies to be involved in the assessment of the application to conduct a clinical trial and to organise the involvement of ethics committees⁶⁸² within the timelines for the authorisation of that clinical trial as set out in this Regulation. Such decisions are a matter of internal organisation for each Member State. When determining the appropriate body or bodies, Member States should ensure the involvement of laypersons, in particular patients or patients' organisations. They should also ensure that the necessary expertise is available. In accordance with international guidelines, the assessment should be done jointly by a reasonable number of persons who collectively have the necessary qualifications and experience. The persons assessing the application should be independent of the sponsor, the clinical trial site, and the investigators involved, as well as free from any other undue influence.”

More specifically, Article 4 of the Clinical Trials Regulation mandates that a clinical trial shall be subject to scientific and ethical review, shall be authorised in accordance with the Clinical Trials Regulation and shall be performed by an ethics committee in

681 Fuchs, supra note 107, 132.

682 Pursuant to the Clinical Trials Regulation Ethics committee means “an independent body established in a Member State in accordance with the law of that Member State and empowered to give opinions for the purposes of this Regulation, taking into account the views of laypersons, in particular patients or patients' organisations”.

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accordance with the law of the Member State concerned.⁶⁸³ Under Article 4, it is the responsibility of Member States to ensure that the timelines and procedures for the review by the ethics committees are compatible with those specified in the Clinical Trials Regulation for the assessment of the application for authorisation of a clinical trial. A Member State has a right refuse to authorise a clinical trial in certain circumstances under Article 8.4.⁶⁸⁴ Such circumstances include aspects relating to the characteristics of and knowledge about the investigational medicinal products; the risks and inconveniences for the subject, non-compliance with the requirements concerning the manufacture and import of investigational medicinal products and auxiliary medicinal products, non-compliance with the labelling requirements; insufficient completeness and adequacy of the investigator's brochure, non-compliance with the requirements for informed consent, non-compliance of the arrangements for rewarding or compensating subjects, non-compliance of the arrangements for recruitment of subjects, non- compliance with the applicable rules for the collection, storage and future use of biological samples of the subject; participation in the clinical trial leading to a subject receiving inferior treatment to normal clinical practice in the Member State concerned; infringement of its national law and considerations of subject safety and data reliability and robustness.

Hence, despite the centralised authorisation procedure, a significant margin of appreciation in ethical questions is left for the ethical committees of the Member States.

In addition, Article 8.4 stipulates that if the reporting Member State finds that the clinical trial is not acceptable in relation to the characteristics of and knowledge about the investigational medicinal products; the risks and inconveniences for the subject, non-compliance with the requirements concerning the manufacturing and import of investigational medicinal products and auxiliary medicinal products, non-compliance with the labelling requirements; insufficient completeness and adequateness of the investigator's brochure, that conclusion shall be deemed to be the conclusion of all Member States concerned. As there is an “opt-out” possibility for a Member State under the Clinical Trials Regulation and the ethical positions of the EU Member States vary, for instance access to hESC as primary materials and opportunities to conduct clinical trials on hESCs is not equally granted in all jurisdictions.

683 Pursuant to Article 4 of the Clinical Trials Regulation “[t]he review by the ethics committee may encompass aspects addressed in Part I of the assessment report for the authorisation of a clinical trial as referred to in Article 6 and in Part II of that assessment report as referred to in Article 7 as appropriate for each Member State concerned. Member States shall ensure that the timelines and procedures for the review by the ethics committees are compatible with the timelines and procedures set out in this Regulation for the assessment of the application for authorisation of a clinical trial.”

684 According to Article 8.4. “ [t]he Member State concerned shall refuse to authorise a clinical trial if it disagrees with the conclusion of the reporting Member State as regards Part I of the assessment report on any of the grounds referred to in the second subparagraph of paragraph 2, or if it finds, on duly justified grounds, that the aspects addressed in Part II of the assessment report are not complied with, or where an ethics committee has issued a negative opinion which in accordance with the law of the Member State concerned is valid for that entire Member State. That Member State shall provide for an appeal procedure in respect of such refusal.”

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7.6.3 Risk-based approach in GMP and clinical trials to foster innovation whilst protecting public health

The risk to subject safety in a clinical trial on ATMPs originates from two primary sources: the ATMP and the trial. A central dilemma is this duality is the question how much of ATMP treatment is product-based and how much is it a treatment process that depends on the clinical and laboratory skills of manufacturers of ATMPs and clinicians administering the product at the bedside. In addition to the classification challenges addressed in Section 7.4 of this study, a further question of classification arises: should the ATMP classification procedure should have more weight in determining what is considered a medicinal product and what is considered medical procedure or practice across Europe? The risk-proportionate approach seems to suggest that risks associated with ATMPs at the early phases of development should be considered especially from a holistic process point of a view (e.g., both at a system level and a trial level).

As a class of medical products, ATMPs are complex. Risks may substantially differ according to the type of ATMP being developed. The risks to the quality of the ATMP in the manufacturing process are higher when the process is multifaceted. ⁶⁸⁵ It should be noted that the final product may also have a high level of variability stemming from the use of biological materials and complex manipulation steps (e.g., cultivation of cells). Special challenges arise when it comes to manufacture and testing of autologous ATMPs in particular. Hence, adequate risk management strategies and tools need to be in place to safeguard quality. These approaches must be tailored to accommodate restrictions on the ATMP manufacturing process. In the draft GMP Guidelines for ATMPs, the European Commission has deemed it is necessary to allow for some flexibility in the application of the GMP requirements so that the ATMP manufacturer can implement the procedures that are most appropriate for specific features of both the manufacturing process and the ATMP. If any such flexibility is applied, it should not in any circumstances compromise the need to ensure the high quality of the ATMP.⁶⁸⁶

The production of IMP ATMPs entails some additional complexity (in comparison to commercial, licensed ATMPs). Special challenges in IMP ATMP manufacture originate among other things from incomplete information about the product as well as the absence of established routines. The European Commission notes in its draft GMP Guidelines for ATMPs that IMP ATMPs, which are also often developed in an academic or hospital environment, operate under quality systems which differ from those usually required for the manufacture of conventional medicinal products.⁶⁸⁷ It is particularly noted that additional flexibility is required in IMP ATMP manufacture for early phases of clinical trials. An acceptable level of quality must also be ensured for such trials, however.

685 European Commission. Consultation Document. Good Manufacturing Practise for Advanced Therapy

Medical Products, 5. Available at:

http://ec.europa.eu/health/files/advtherapies/2015_pc/publ_cons_doc_2015.pdf. Accessed 12 June 2016.

686 Op. cit., 6.

687 Ibid.

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As discussed in Section 7.5.3, the risk-based approach does not allow for derogations from the marketing authorisation or clinical trial requirements. By contrast, when ATMP-specific flexibility applies; it requires the manufacturer to ensure that additional measures are in place (in addition to those proposed in the GMP guidelines) if that is necessary given the particular risks of the ATMP. Therefore, in order to take all potential risks into consideration, the ATMP manufacturer is required to identify the risk control measures that are most appropriate in each case.⁶⁸⁸

The public consultation launched by DG SANTE seeks to get the perspectives of stakeholders and other interested parties on the document regarding "Risk proportionate approaches in clinical trials" which has been developed in preparation for the implementation of the Clinical Trials Regulation.⁶⁸⁹ Despite this consultation document not specifically addressing the risk aspects of ATMPs (further clarifications regarding risk management of ATMPs in clinical trials are needed), some general observations can be made. The approach adopted in the consultation document not only requires consideration of risks in clinical trials at the system level (e.g., facilities, standard operating procedures, computer systems, and personnel) but also at the trial level (e.g., in terms of investigational medical product, trial design, and data collection and recording). In addition to the risks relating to the IMP ATMP, risks may arise from intervention that may adversely affect the clinical trial subjects. Such risks may include failure to comply with the clinical procedures specified by the protocol, failure to obtain fully informed consent or to protect personal data, data integrity, the reliability of the results and their scientific use or validity. Pursuant to the European Commission’s proposal, a risk based quality management system should consist of the following consecutive steps: (1) risk identification; (2) risk evaluation; (3) risk control; (4) risk review; (5) risk communication and (6) risk reporting. ⁶⁹⁰ Nevertheless, no ATMP specific clarifications have been provided regarding these elements of the quality control process in the consultation documents on risk based approaches in clinical trials.

(Yet, some of these issues are addressed from the perspective of adaptations to GMP requirements in the draft GMP Guidelines as discussed in Section 7.5.3).

688 Ibid.

689 European Commission, supra note 425.

690 Op. cit., 6.

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Figure 5. Phases of risk-based quality management in clinical trials

Reference: European Commission’s proposal, a risk based quality management system, supra note 425, 6.

The proposed risk-based approach allows for some adaptions to low intervention clinical trials, such as those deemed to pose only a minimal additional risk to subject safety compared to normal clinical practice. Such trials, defined in Article 2(3) of the Clinical Trials Regulation must meet all of the following conditions: (a) the investigational medicinal products, excluding placebos, are authorised; (b) according to the protocol of the clinical trial, (i) the investigational medicinal products are used in accordance with the terms of the marketing authorisation; or (ii) the use of the investigational medicinal products is evidence-based and supported by published scientific evidence on the safety and efficacy of those investigational medicinal products in any of the Member States concerned; and (c) the additional diagnostic or monitoring procedures do not pose more than minimal additional risk or burden to the safety of the subjects compared to normal clinical practice in any Member State concerned. To safeguard the subject safety of low-intervention clinical trials, they are subject to the same evaluation process as any other clinical trial, but with adapted dossier requirements.⁶⁹¹

Given that most of the ATMPs are unauthorised and still in the early phases of clinical trials, very few of them may meet these criteria. In contrast, developers of ATMPs should take the particularities of each investigational product into account when developing a risk-based quality management system for a trial. Because of their complex nature, some products such as substantially manipulated ATMPs may indeed be considered as higher risk products that actually necessitate additional safeguards before they can be brought to clinical trials involving humans.

Risk identification and risk evaluation are crucial in managing and mitigating the risks when setting up a quality management system for a trial involving IMP ATMPs.

Generally speaking, pursuant to EMA’s reflection paper on risk-based quality management of clinical trials, the risk evaluation assessment process covers following aspects i) the likelihood of potential hazards associated with the trial, ii) the impact, if

691 Op. cit., 6.

Identification

Evaluation

Control

Review

Communication

Reporting

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they could occur, of these hazards on the safety of subjects and data integrity and iii) the extent to which such hazards would be detectable.⁶⁹² In a risk-based quality management system, a mitigation strategy (such as monitoring measures) for each identified risk must be implemented or alternatively a determination made that the risk can be accepted.⁶⁹³ The risk identification and risk evaluation should consider any and

they could occur, of these hazards on the safety of subjects and data integrity and iii) the extent to which such hazards would be detectable.⁶⁹² In a risk-based quality management system, a mitigation strategy (such as monitoring measures) for each identified risk must be implemented or alternatively a determination made that the risk can be accepted.⁶⁹³ The risk identification and risk evaluation should consider any and

In document Commercialisation of Advanced Therapies : A Study of the EU Regulation on Advanced Therapy Medical Products (sivua 165-175)