Types of research

The guidelines distinguish between different types of research with medical devices.

If the research involves medical devices without CE marking, the sponsor must have: (i) an authorisation from the AEMPS; (ii) a favourable opinion from an Ethics Committee for Research on Medicinal Products (CEIm), which will be unique and binding on all the centres involved in the study; and (iii) the agreement of the management of each centre, which is usually obtained when the relevant contract is signed. The same requirements apply if the device is CE marked but some aspect is being evaluated outside the manufacturer’s intended purpose.

On the other hand, if the medical device under investigation is CE marked and used in accordance with its instructions for use and within its intended purpose, the same requirements apply, with the exception of authorisation by the AEMPS. However, if patients are to be subjected to additional, invasive or burdensome procedures in addition to those used under normal conditions of use, the study must be notified to the AEMPS.

Finally, if the research is conducted with a medical device, without a CE marking or with a CE marking but outside its intended purpose, even if the sponsor’s intention is not to use the research to assess the product’s conformity for obtaining the CE marking, the sponsor must consult the AEMPS on the procedure to be followed.

Authorisation procedure

In cases where AEMPS approval is mandatory, the sponsor must submit several documents. The most important documents are: (i) the investigator’s manual, which contains clinical and non-clinical information on the product and on any medicinal substances, blood derivatives or cell or tissue-based products that may be incorporated in the medical device; and (ii) the clinical research protocol, similar to the clinical trial protocol for medicinal products, with information on the justification, objectives, design and methodology of the research, as well as its monitoring, conduct and registration. The AEMPS also recommends that the most up-to-date information on the regulatory status of the product in other countries be provided. Once all the documents have been submitted, the AEMPS has a period of 45 calendar days to authorise the study, if necessary, with the possibility of extending this period by a further 20 days to request expert opinions, without prejudice to possible “clock stops” for the correction of deficiencies or the submission of additional documents. 

Manufacture and import

According to the AEMPS, if the manufacturing company is located in Spain, it is not necessary to have a prior operating licence to manufacture devices intended for clinical research, although it is necessary to ensure that they have been properly manufactured. On the other hand, an import licence is not required for a company importing medical devices for use in clinical research in Spain. 

The promoter and other involved parties

As in the case of trials with medicinal products, if the sponsor is not established in an EU Member State, the sponsor must appoint a representative established in an EU Member State. In all cases, the sponsor must appoint a monitor who is independent of the trial site to ensure that the trial is conducted in accordance with the protocol, good clinical practice, and applicable regulations. In addition, if the sponsor is not the device manufacturer, the manufacturer’s contact information must be provided.

Other requirements

Documents related to the study must be in Spanish. However, the clinical research protocol and investigator’s plan may be accepted in English unless otherwise specified by the CEIm. The AEMPS always reserves the right to require a translation into Spanish.

In the case of research with devices without a CE marking, or devices  with a CE marking but outside its intended purpose, mechanisms should be put in place to ensure that patients are compensated for any harm that may result from their participation in the research, either in the form of insurance, a guarantee, or a similar mechanism, equivalent in purpose and commensurate with the nature and extent of the risk.

The documents constituting the master file of a research shall be kept for at least 10 years after the investigation has been completed or, if the device is subsequently placed on the market, for at least 10 years after the last unit of the device has been placed on the market. In the case of implantable devices, the period shall be at least 15 years.

La entrada Updating the rules for conducting medical device studies in Spain aparece primero en Faus Moliner.

In March 2017, under Law 19/2013, on Transparency, Access to Public Information and Good Governance, an association of consumers and users requested the Spanish Ministry of Health,  Social Services and Equality (MOH) to provide them with statistics of prescription and annual cost of certain medicinal products (price, number of prescriptions, total annual cost, financed cost); as well as with the raw data of the clinical trials on the basis of which their marketing authorisation was granted. Given the refusal of the MOH to provide such information, Scabelum exercised its right to submit a complaint before the CTBG.

Access to economic data

In its allegations before the CTBG, the MOH pointed out that the information could not be provided since it could be detrimental to legitimate economic and commercial interests, invoking therefore one of the limits that permit refusal of access in accordance with Law 19/2013.

The CTBG, in its resolution, criticizes the fact that the MOH refuses access without properly explaining the reasons for which it understands that providing access could be detrimental to the economic and commercial interests of a company, reiterating its doctrine in the sense that, in order to benefit from this derogation foreseen in Law 19/2013, the administration must apply criteria of proportionality and must properly analyse the circumstances of each specific case.

The CTBG understands that providing the association with the requested information cannot cause any harm to the companies involved due to its statistical nature and because the MOH publishes, on its web page, statistics of consumption and pharmaceutical expenditure based on prescriptions of the National Health System.

On the other hand, we should recall that the doctrine of the CTBG (Resolution of 5 of November of 2015) is that the MOH must not provide access to the economic and financial data that the pharmaceutical company has offered to the administration when requesting the authorisation for the price of the product.

Access to the clinical trials data

Regarding the clinical trials that justify the marketing authorisation, the CTBG establishes that it must be the AEMPS who must respond to the request as it is the competent body, highlighting that the MOH should have transferred the request to the AEMPS for processing. Likewise, the CTBG recalls that the Spanish registry for clinical trials exists since January 2016 and that it contains information about the way the trial is conducted and also information regarding its results.

La entrada Access to the data regarding the cost of medicinal products and clinical trials data aparece primero en Faus Moliner.

Simplification of the process

The procedure to obtain the authorisation to start a trial, or to make a substantial change to the conditions under which such authorisation is originally granted, have been simplified considerably, in particular for low-intervention clinical trials. The most noteworthy new feature, in addition to a shortening of timescales, is that an opinion need only be sought from one Ethics Committee (now known as Research Ethics Committee) rather than one per participating centre, as had been the case up until now. This change will lead to obvious time savings in the procedure, in addition to a reduction in costs as only one fee shall be paid as part of the assessment of the trial, regardless of whether several Committees are involved in said process.

Importance of the contract

Another important new aspect involves the contract that the sponsor must sign with each centre participating in the trial. Historically, the negotiation and signature of contracts has been a nightmare for sponsors, often leading to delays in starting trials. The Royal Decree seeks to speed up this process by implementing two measures. First, it calls on the competent health authorities to agree on just one valid contract template for the entire National Health System (SNS), the drafting of which is based on the general principles established by the Interterritorial Council of the SNS. And second, it allows for the contract to be executed at any time, and not solely upon authorisation of the trial, as had been the case up until now. In the event that the contract is signed before the trial is authorised, the regulation sets out that the contract will not become effective until authorisation is obtained.

Figure of the sponsor

The contract is particularly important when the sponsor decides to delegate all or part of its duties to a third party, such as a CRO. Thus, special care must be taken to appropriately document which tasks have been delegated and the scope of liabilities must be defined.

La entrada New rules for carrying out clinical trials in Spain: in a faster, safer and more transparent way aparece primero en Faus Moliner.

As a result of an anonymous complaint made before the Spanish Agency of Medicinal Products and Medical Devices (AEMPS in Spanish), an infringement procedure was initiated against a physician claiming that he had carried out a clinical trial, acting as sponsor and principal investigator, without obtaining prior approval, without having received a favorable ruling from the CEIC, and having obtained the informed consent of the patients by providing them with information that was not accurate. The Autonomous Region of Madrid imposed a fine of 216.003 Euros. The judgment confirms the fine.

Differences between a trial and an observational study

The core of the discussion before the Court was establishing whether the study of Dr. Soriano was a trial or a prospective observational study. The judges analyzed in detail the differences between both concepts; and they came to the conclusion that when a medicine is used under conditions different from those that are set forth in its SmPC one cannot speak of a post-authorization observational study. In this sense, the judgment points out that in an observational study medicines must be prescribed in accordance with the normal conditions of clinical practice, and that according to the rules governing these studies such normal conditions are those established in the marketing authorization.

Before reaching this conclusion, the judgment establishes that a medicinal product used under conditions different from those authorized becomes a medicinal product under investigation; reproducing thus the provisions of Royal Decree 1015/2009. Therefore, it is convenient that those who use medicinal products under conditions different from those authorized adjust strictly to legal rules and handle with the utmost care any activity that might be considered as clinical investigation. As the judgment says neither the medical practice nor the professional freedom of prescription of the physician protect, under any circumstances, the performance of unauthorized clinical trials.

Off label use

On the other hand, the judgment is a wake-up-call for those who favor the use of medicinal products under not authorized conditions. The judgment refers to this use recalling the provisions of Royal Decree-law 16/2012 regarding the sustainability of the National Health System, highlighting that the prescription of medicinal products and medical devices must be made in the most adequate way in benefit of the patients and that off label use must be authorized previously by the commission responsible for the therapeutic protocols in each Autonomous Region.

The Court also recalls that this applies even if the medicinal product is used in the approved indications but with a dosage different from the one authorized.

La entrada Important fine to an investigator that promoted a clinical trial without administrative approval aparece primero en Faus Moliner.

En la Unión Europea esta regulación fue objeto de armonización a través de la Directiva 2001/20/CE, de 4 de abril que, como es sabido, España traspuso a su ordenamiento interno a través del Real Decreto 223/2004, de 6 de febrero, por el que se regulan los ensayos clínicos con medicamentos actualmente en vigor.

El proyecto de Real Decreto ahora en tramitación (bajo el título “Real Decreto por el que se regulan los ensayos clínicos con medicamentos, los comités de ética de la investigación con medicamentos y el registro de estudios clínicos”) tiene precisamente como finalidad principal adaptar la regulación española a toda aquella normativa europea que se va venido aprobando desde que entró en vigor el mencionado Real Decreto 223/2004, consolidando todas las novedades habidas en una única norma. En cierto modo ello supone un avance a todo cuanto al fin terminará regulando el futuro Reglamento Europeo sobre ensayos clínicos de medicamentos de uso humano, que se prevé vea la luz este próximo 2014.

Entre las novedades más relevantes del proyecto cabe citar, en primer lugar, la simplificación del procedimiento de autorización de los ensayos clínicos, que se logrará fundamentalmente a través de una evaluación coordinada del ensayo por parte de la Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) y el CEIm (Comité de Ética de la Investigación con medicamentos). Los CEIm, que en este punto vendrán a sustituir a los antiguos CEIC, serán los órganos encargados de evaluar los proyectos de investigación con medicamentos y también con productos sanitarios, y de emitir el tan ansiado dictamen único, que se espera acabe con el largo periplo burocrático que debían seguir quienes pretendían investigar con medicamentos en España. Asimismo, se implementan otras medidas de importante calado, tales como el establecimiento de un único punto de contacto para el promotor en sus relaciones con la AEMPS, los CEIm y las autoridades competentes de las Comunidades Autónomas, o la utilización de medios electrónicos en las solicitudes y comunicaciones entre la AEMPS, el CEIm, el promotor y demás agentes implicados. Otra novedad digna de mención es la introducción de la figura del llamado “ensayo clínico de bajo riesgo”, respecto del que se flexibilizan los requisitos necesarios para su puesta en marcha.

Por otra parte, también se posibilita el acceso del público a la información relevante de los ensayos clínicos, mediante la creación del Registro Español de estudios clínicos (REec) titularidad de la AEMPS, potenciando así la confianza de la sociedad en la investigación como forma de favorecer su progreso. Por último, pero no por ello menos importante, se insiste en la necesidad de acordar un modelo de contrato único válido para todo el Sistema Nacional de Salud, y evitar así las dilaciones que habitualmente se producen en la negociación de los innumerables modelos existentes en la actualidad. Auguramos que será ésta una cuestión difícil de solventar, por los intereses a menudo contrapuestos de los diferentes agentes implicados. Pero aun así, a nuestro juicio, el proyecto en tramitación sin duda supone un notable salto cualitativo en orden a facilitar el desarrollo de la actividad investigadora en nuestro país, al mismo tiempo que se garantiza un adecuado grado de protección y respeto a los derechos de los sujetos que participan en estas investigaciones.

La entrada Un impulso a la investigación clínica en España aparece primero en Faus Moliner.

Through these changes the Ministry aims at  anticipating the new European regulation on this matter which is foreseen to be issued in 2014, and which seeks to facilitate research in the  territory of the European Union. Due to its interest, we will briefly summarize some of the most relevant novelties.

Simplification of procedures

The main objective of the draft is to simplify the procedure for obtaining the authorization necessary to implement a clinical trial in Spain. With this aim, it is foreseen to improve the coordination between the Spanish Agency for Medicinal Products and Medical Devices (AEMPS) and the new Evaluation Committees for Research with medicinal products –that will progressively replace the current Clinical Research Ethics Committees– in order to avoid duplicities in the process of evaluation of the trial.

Likewise, the long expected “single ruling” shall be finally implemented. The principle of mutual recognition, deeply ingrained in European pharmaceutical law, has finally arrived to the rulings with regard to clinical trials. In this way, the ruling issued by the Evaluation Committees for Research with medicinal products chosen by the sponsor shall have to be accepted by the rest of the committees involved in the trial. Other measures along the same line are the introduction of the figure of the “low risk clinical trial”, for which there will be less burdensome requirements, the introduction of a single point of contact between the sponsor and the authorities, or the generalization of the use of electronic media in the communications between the two.

More transparency

More and better information on clinical trials carried out in our country will be put at the disposal of the public, through the creation of a state registry of clinical trials. Such registry, which will be managed by the AEMPS, shall allow for more transparency and will provide interested patients with the possibility to participate in the trials that will be started.

A single contract model

The plan to implement a single contract model to be used in all public hospitals that depend on the National Health System should also be emphasized.

It is moreover foreseen that the signing of such  contract between the centre and the sponsor should take place in a period of 60 days. However, and since there are no implications involved in case that such term is exceeded, we will have to wait for the approval of the draft to see how effective this mandate is.

La entrada The Ministry releases the draft for the new regulation on trials with medicinal products and medical devices aparece primero en Faus Moliner.