Medtech’s mini guide to…centralized and decentralized regulatory procedures

The European Parliament is currently considering the merits and drawbacks of centralized and decentralized pharmaceutical-style procedures conducted through the European Medicines Agency for certain high-risk medical devices.

Parliament’s rapporteur on the European Commission’s proposed Medical Device Regulation, Dagmar Roth-Behrendt, has issued a draft report where she controversially proposes a centralized procedure for “innovative” (this word was not defined) high-risk devices that are implantable; utilize non-viable tissues or cells of animal or human origin; incorporate ancillary medicinal substances; and are intended to administer medicinal products.

She also proposes a decentralized procedure, slightly altered from the pharma original on which it is based, which would apply to all the aforementioned products but which are not considered “innovative”, as well as to Class III devices. This decentralized procedure would involve the loss of access to the whole of the EEA single market as is presently possible through the current EU device requirements.

It is still far from certain if Ms Roth-Behrendt’s proposals will go through. Overall, they have met with strong resistance from the medical technology industry, which has long opposed a premarket authorization system for medical devices on the grounds that the costs and delays it incurs would be unsustainable to device manufacturers.

In the devices sector, technology moves forward at such a pace that products tend to remain, on average, on the market for a much shorter lifetime than pharmaceuticals. To match the significant discrepancy in life expectancy of these products, at present it takes companies an average of 18 months to get through the regulatory requirements for medical devices, and – taking account of the long preclinical and clinical development period plus the regulatory approval process – anything up to 10 years for pharmaceuticals. Moreover, the vast majority of medical device manufacturers are SMEs – some 85%. Where they are not already active in the pharma area, these companies would struggle to meet the huge costs involved in adapting to the pharmaceutical regulatory model for some or all of their products.

But what exactly is involved? What framework might the medical device sector have to fit into, how do the traditional pharma processes work, and what kind of investments and changes are involved?

These are the questions Clinica’s Amanda Maxwell put forward to Ian Schofield, principal analyst at Informa and specialist in EU pharma regulatory affairs, to get a better understanding of these new procedures and find out what their likely impact would be on devices.

Clinica: Can you please explain the main EU legal instruments that regulate the pharma sector and the EU legal context?

Ian Schofield: Pharmaceuticals are subject to EU legislation – mainly Directives and Regulations – in a variety of areas such as marketing authorizations, clinical trials, pharmacovigilance, manufacturing standards, distribution, and pricing and reimbursement.

Clinica: How does the regulatory approach for pharmaceuticals differ from the New Approach basis on which the Medical Device Directives are built?

IS: In contrast to the situation with medical devices, where the manufacturer has ultimate responsibility for certifying that the device is in conformity with the necessary requirements, no medicinal product can be placed on market in the EU without first obtaining a marketing authorization (although there are some exceptions to this rule in some countries, such as compassionate use under the responsibility of the prescribing doctor).

Clinica: How does a company go about making a marketing authorization application?

IS: For pharmaceuticals, the marketing authorization dossier is assembled using a template drawn up by the International Conference on Harmonization (ICH), called the Common Technical Document.

The dossier is submitted to the relevant regulatory body: either the European Medicines Agency when a pan-EU marketing authorization (MA) is required through the centralized procedure, or a national competent authority (medicines agency) when MAs are sought in individual countries through the decentralized or mutual recognition procedures. Pan-EU MAs are issued by the European Commission, and national approvals by the relevant national regulatory body. For pharma products, the dossier includes sections on quality (drug substance, manufacturing data, characterization, stability etc), non-clinical trial data (pharmacology, toxicology, pharmacokinetics/pharmacodynamics), and clinical trial data (clinical pharmacology, efficacy and safety).

Clinica: What dictates whether a medicinal product goes through the centralized or decentralized procedure?

IS: The centralized procedure is intended to be used mainly for new active substances. It is mandatory for certain classes of drug: biologicals (originators and biosimilars), orphan drugs, and products containing substances for treating AIDS, cancer, neurodegenerative disorders and diabetes.

The centralized procedure can also be used for the approval of generic drugs and certain medicines for pediatric use. The remainder of pharmaceuticals go through either the decentralized procedure or the mutual recognition procedure.

Clinica: The current proposal from the European Parliament is that “innovative” high-risk devices that are implantable, utilize non-viable tissues or cells of animal or human origin, that incorporate ancillary medicinal substances and that are intended to administer medicinal products would also go through the centralized procedure. Can you briefly summarize the centralized procedure to give the device industry some idea of what is likely to be involved?

IS: Under the centralized procedure, the EMA’s scientific committee, the CHMP (Committee on Medicinal Products for Human Use), conducts the evaluation within a period of 210 days, at the end of which it issues a scientific opinion either recommending, or advising against, marketing authorization.

If the opinion is positive, it goes to the European Commission to be converted into a marketing authorization within 67 days. If it is negative, the company either accepts the opinion and withdraws the product from the evaluation process, or works with the CHMP to generate new data to support marketing authorization.

Once a centralized MA is issued, it is immediately valid throughout the EU, although actual access to the market depends on factors such as pricing and reimbursement negotiations, which vary from one country to another.

Clinica: What other marketing authorization applications apply to pharmaceuticals and when? And what are requirements for the decentralized procedure, in particular, since this is being considered for all of the same devices as mentioned for consideration for the centralized procedures, but where not considered “innovative”, and to Class III devices as well?

IS: For pharma products that do not fall under the mandatory scope of the CP and the EMA, there are three other options for obtaining marketing approval.

Under the first, the national procedure, the company may apply to just one national regulatory body for marketing authorization because it only wants to market the drug in that country.

If, however, the company wants to market the product in more than one EU country, but not in all, it can choose one of the other two options: either the mutual recognition procedure (MRP) or the decentralized procedure (DCP).

Under the mutual recognition procedure, a “reference member state” is chosen to conduct the first assessment. If that country’s regulatory agency decides to issue a marketing authorization (MA), the company then applies to the remainder of its chosen markets (concerned member states, or CMSs), asking them to recognize the first approval.

Under the decentralized procedure, the reference member state conducts the evaluation and produces an assessment report but does not actually issue an MA. Instead, the chosen CMSs get together to agree on the assessment report, and once agreement has been reached they each issue a marketing authorization.

Clinica: Does this therefore mean that Dagmar Roth-Behrendt is proposing in her draft report rather a mish-mash of the pharma requirements?

IS: As far as I can see, Article 41e of Ms Roth-Behrendt’s draft report outlines a decentralized procedure that combines the current MRP and DCP. So, where a product already has a national authorization, the company can ask specified concerned member states to recognize that authorization (whereby the country that initially granted that authorization becomes the reference member state) – this mirrors the MRP.

Where there is no existing authorization, the company will specify a reference member state to draft an assessment report on the product and send it to the CMS for approval, after which (if they agree on approval) they will each issue a marketing authorization (as in the DCP).

Clinica: How well do the centralized and decentralized procedures work, in the view of the pharma industry? What are the strengths of such a system and what are the perceived weaknesses or elements that industry would like to change?

IS: The centralized procedure generally works very smoothly, and is preferred by manufacturers seeking, for example, pan-EU approval of a novel therapy that is to be marketed in all, or nearly all, member states. Its strength is that it provides an authorization that is immediately valid across the EU. One disadvantage is that if a marketing authorization application is rejected by the CHMP, the product then cannot be marketed anywhere in the EU. This means that in some cases companies might prefer to take the product through a non-centralized procedure, so that it may gain approval in at least some countries.

The advantage of the mutual recognition system is that a company can choose the countries where it wants to apply for approval based on, say, the reputation or expertise of a particular agency for evaluating specific types of product. The drawback is that it can be an unpredictable process, with CMSs often disagreeing with the initial authorization decision and refusing to recognize it, leading to lengthy arbitration procedures.

It was because of these drawbacks that the decentralized procedure was introduced during the review of the pharmaceutical legislation in 2004. This is a more rapid and predictable process, whereby the MAA is submitted to several member states at the same time, with one being chosen as the RMS. Once the RMS has produced an assessment report that the others can agree on, marketing authorizations are granted in all the countries involved. This means that any disagreements and uncertainties over the dossier can be dealt with at an earlier stage, thereby helping to avoid arbitration procedures.

Clinica: There is a proposal for a Committee for the Authorisation of Medical Devices at the EMA. There are suggestions that this will mimic the modus operandi of the CHMP. Can you explain how the CHMP works?

IS: The CHMP, as the core scientific committee of the EMA, conducts the initial assessment of all new drugs submitted to the agency for centralized approval. Its assessments are based on purely scientific criteria, and are intended to assess the safety, quality and efficacy of drugs, and to ensure that they have, and retain, a positive benefit-risk balance.

It plays an important role in the system of pharmacovigilance by monitoring reports of possible safety issues and making recommendations to the European Commission on, for example, changes to the marketing authorization or withdrawal from the market. It can where necessary issue an “urgent safety restriction”.

Before the approval dossier is filed, the CHMP may meet the drug sponsor to discuss the dossier and offer scientific advice, for example on complex submissions such as biologics.

It is supported in its role by various working groups and other committees such as those on pharmacovigilance risk assessment, advanced therapies, pediatrics and biosimilar medicines.

Once a drug is authorized, the CHMP publishes a European Public Assessment Report (EPAR) explaining the scientific grounds for its opinion, as well as a summary of product characteristics for doctors and a patient information leaflet. It also helps in producing scientific and regulatory guidance, and works with international partners on efforts to harmonize regulatory requirements across regions.

It acts as the arbitration body where there are disagreements between member states over marketing authorizations in the MRP and DCP, and in referral procedures involving safety issues with medicines.

Clinica: In the light of this explanation about the CHMP, in your opinion, how well would the EMA be able to cope with additional responsibilities for such a broad range of high-risk medical devices? What would it need to make this work?

IS: The EMA is already struggling under an increasingly heavy workload, particularly as a result of its added responsibilities under the new pharmacovigilance legislation, which among other things has required it to establish a dedicated Pharmacovigilance Risk Assessment Committee (PRAC).

Moreover, it is working with very limited financial resources (partly as a result of budgetary belt-tightening at EU level), and while a new fee structure has been proposed to fund the new pharmacovigilance activities, this has not yet been put in place.

On the other hand, the EMA does have some experience in this area. It can be consulted on medical devices that containing medicinal products, and since September 2012 it is publishing public assessment reports on pharmaceutical and biological products used in devices (although these reports have no bearing on whether a medical device is approved for a CE marking). Moreover, through the Committee for Advanced Therapies (CAT), the EMA works with the Medical Devices Notified Body Collaboration Group, including on helping to co-ordinate processes and guidance for the consultation of an NB for medical devices when the CAT assesses a combined ATMP/MD.

There is also the argument that many member state medicines agencies regulate both pharmaceuticals and medical devices without any apparent problems.

Clinica: What would this require in terms of additional resources at the EMA?

IS: At EU level a significant increase in staff, experts and financial resources would be necessary if the agency were to take on the evaluation of high-risk medical devices and to set up and operate a new scientific committee.

It would, after all, be responsible not only for initial centralized product evaluations, but also for any subsequent safety, quality and efficacy issues raised with those products, and for drafting guidance, offering scientific advice, etc, as it does now for medicinal products.

The additional financial resources might, in part, come from the EU budget, but it is likely that a substantial proportion would need to be raised from device industry fees.

Clinica: Parliament is also proposing that the EMA would enter information on centralised applications and authorizations for market approval in an electronic system on marketing authorizations set up by the Commission, in collaboration with the Member States, with Member States entering the information relating to the decentralised procedure. Is this how the system works in the pharma sector? And does the EMA, in your view, have the resources for this?

IS: EudraPharm, the medicinal product database launched in 2006 and accessible to the public since 2007, gives online access to information on all human and veterinary drugs approved for marketing in the EU, including the Summary of Product Characteristics (SmPC), the patient information leaflet (PIL) and the product labeling.

EudraPharm also provides access to the EU Clinical Trials Register, which contains data taken from the clinical trials database, EudraCT.

The information in EudraPharm relates mainly to products approved via the centralized procedure, although there is also information on some medicines authorized by national regulators.

Assuming that medical device information would also be included in EudraPharm in some way, adding this functionality would not seem to represent a significant added burden.

However, the EMA does not publish information on centralized marketing authorization applications, and doing so for device applications would represent a significant departure from current practice.

Clinica: Parliament is suggesting that the Committee for the Authorisation of Medical Devices may request samples or make unannounced inspections to the manufacturing site of the medical device, to complete its examination of an application through the centralized procedure. Is this also prescribed under EU pharma rules?

IS: A GMP inspection may be carried out when an application for a marketing authorization is received, but this is not compulsory. The aim of the inspection is to check GMP compliance regarding the medicine in question, or to investigate a specific matter arising from the assessment of the application. Inspections also take place periodically after the MA is granted.

Samples for testing are not required when the MA application is submitted, although under Regulation 726/2004 the CMHP may request the testing of samples of the product and/or its ingredients during the assessment process. In this case the rapporteur for the products will specify the test protocol, and sampling and testing will be conducted by the EMA together with the European Directorate for the Quality of Medicines and Healthcare (EDQM).

The EMA also co-ordinates a general sampling and testing program that is intended to monitor the quality of centrally authorized medicines on the market on an ongoing basis. Products are usually selected for testing three years after they have been authorized, with around 40 products a year being tested.

Clinica: Are there any final observations that you would like to add?

IS: The regulatory process is only one part of a product reaching the market. Just as with medical devices, another hurdle is pricing and reimbursement.

While the pricing and reimbursement of medicines remains a member state responsibility under the subsidiarity principle, member states must abide by the price transparency directive, which stipulates maximum pricing and reimbursement times, the need for appeal mechanisms , and so on. Pricing and reimbursement times, not to mention actual price levels, vary widely from one country to another, and market access is now increasingly dependent on cost-benefit evaluations conducted by health technology assessment (HTA) bodies such as the UK’s NICE and Germany’s IQWiG.

The EU legislation also provides a number of protections for pharmaceuticals, such as a data exclusivity period for originator drugs (during which no generic version can be approved) and a marketing exclusivity period (during which no generic can be marketed), as well as supplementary protection certificates (SPCs) that extend effective patent life, and pediatric extensions that lengthen the SPC period. Like other inventions, medicines can be covered by patents granted by the European Patent Office, which must be validated in each national patent office and litigated in the national courts, although a new patent with unitary effect is being introduced, probably from 2014, together with a unified patent court.