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Safety after launch: how post-market surveillance in medicines compares with monitoring in medical devices
The path to market launch for both medicinal products (aka medicines, drugs or pharmaceutical products) and medical devices is lengthy and stringent – and rightly so, as we need to ensure that the risks of the medical products (i.e. medicinal product, device, or combination product) to patients are minimised. But what happens once the medical product is approved for use in the “real world”; is there an appropriate “safety net” to protect patients?
Once a medical device is in the market, it may be used by untrained or inexperienced users for example, or a drug may be prescribed to a patient with additional or even undiagnosed health complications. There is growing emphasis on post-market surveillance (PMS) – monitoring the safety of a medicinal product or medical device in real world use – as part of the pharmacovigilance process.
In this article we look at the approach to PMS in Europe, for medicinal products versus medical devices.
Safety in numbers
Like the practice of medicine itself, the premise of all medicines and medical devices is that they should “do no harm”. However, we recognise the need for new therapy options – drug and device – to progress disease management and make life better for patients. The trick is to get the balance right: innovation to provide improved healthcare, but without throwing patient safety to the wind.
The journey towards a safe medicine or medical device begins early. In the development stage, pharmaceutical and medical device manufacturers face the challenge of ensuring stringent regulatory processes are followed for assessing the risk of a product. But, despite the prevailing standards and regulations for assuring effectiveness and safety, there remains a level of risk attached to drugs and devices approved for market release.
Take the case of a drug in development, the de facto approach to testing efficacy and safety is the clinical trial, but the number of subjects recruited into a clinical trial is usually small relative to the total patient population. The patient cohort is usually picked with specific criteria in mind, representative of the indication that the drug needs to address, but without complicating comorbidities. Special groups are usually excluded, for example pregnant women, children, or those with renal or hepatic disorders. The clinical testing period is often short compared to the relevant course of therapy – this is particularly the case with drugs addressing chronic conditions such as rheumatoid arthritis, diabetes and asthma. The limitations on the data obtainable in clinical trials could potentially result in a limited – or distorted – picture of safety (and also efficacy).
Once a drug is released onto the market for use by a patient group which includes those not represented in clinical trials, the safety picture may change. The use of medicines over longer time periods by a wider population can lead to adverse effects not seen in the clinical trial population. High-profile examples in which this was the case include Vioxx (an osteoarthritic/acute pain medication) and Avandia (an anti-diabetic), which both remained in the market for some time before a pattern of safety problems was detected.
Safety problems are by no means limited to drugs; they can also occur in medical devices, as in the recent well-publicised case concerning silicone breast implants. It took a UK report (June 2012) to expose faulty implants manufactured by French company Poly Implant Prostheses (PIP), which had double the rupture rate of other implants.
So how do manufacturers get important medicines and devices into market in a timely fashion whilst protecting patients and supporting prescribers in clinical settings? The answer is essentially, “safety in numbers”; legislative effort is required to demonstrate continued safe use of a medical product by gathering clinically relevant data – specifically, real-world post-authorisation monitoring information. The routes taken by drug and medical device manufacturers are different, but the end result should bethe same: safer healthcare delivery.
Post-market surveillance of medicinal products
Routine (mandatory) risk minimisation applies to all medicines. This requires all medicines to have the following combination of elements:
- The Summary of Product Characteristics (or SmPC) – essential information for a healthcare professional on how to use the medicine, including when the medicine should not be used and special warnings and precautions for use.
- Patient Information leaflet (or PIL).
- Packaging labelling.
- Pack size and design.
- Legal (prescription) status of drug.
Additional Risk Minimisation Measures (aRMMs) are used to reduce the occurrence of known risks associated with medicines1. Subject to additional monitoring are any medicines:
- Authorised on or after 1 January 2011 that contain a new active substance.
- That are characterised as a biological medicine such as a vaccine or large protein biological substances.
- Which require further studies i.e. which need to provide data on long term use of the medicine.
- Which have been given conditional approval under exceptional circumstances, for example, if the product is designed to treat very rare indications where evidence is likely to be difficult to collect, or it would be contrary to acceptable principles of medical ethics to collect such evidence.
proper application, intended by the manufacturer to be used for human beings for the purpose of:
- Diagnosis, prevention, monitoring, treatment or alleviation of disease.
- Diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap.
- Investigation, replacement or modification of the anatomy or of a physiological process.
- Control of conception.
and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted by such means.
Medicinal Product (Directive 65/65/EEC)
Any substance or combination of substances presented for treating or preventing disease in human beings or animals. Any substance or combination of substances which may be administered to human beings or animals with a view to making a medical diagnosis or to restoring, correcting or modifying physiological functions in human beings or in animals is likewise considered a medicinal product.
What do arMMs consist of in practice?
This varies from medicine to medicine, and will depend on the identified and potential risks that have been revealed in clinical trials and other research stages and which must be documented in the medicine’s risk management plan. An aRMM can be as straightforward as active communications to healthcare professionals (colloquially known as “Dear Doctor” letters”). However, some drugs warrant more complex or onerous aRMMs.
One example is Otsuka Pharmaceutical’s Jinarc® (tolvaptan), a pharmaceutical therapy available in Europe which is able to target autosomal dominant polycystic kidney disease (ADPKD) in patients. A chronic and progressive genetic disease, ADPKD causes a proliferation of cysts and growths in the kidneys and results in complications that include chronic and acute pain, hypertension and kidney failure, requiring dialysis or renal transplant. The disease is thought to affect between 3-4 people in every 10,000 – around 205,000 people in Europe2.
Additional monitoring that Otsuka as market authorisation holder has to carry out includes ensuring that all healthcare professionals who are expected to prescribe Jinarc have access to an educational package (a summary of product characteristics and training material) aimed at highlighting the potential risk of liver toxicity and providing guidance on managing this risk.
The importance of pregnancy prevention prior to initiation of, and during treatment with, Jinarc is also included in the education of healthcare professionals. The aRMMs for Jinarc also include an information pack for patients/carers, containing not only the PIL, but educational material and a patient alert card. These information elements emphasise the risks associated with taking Jinarc and appropriate advice should the symptoms occur.
Another requirement of Otsuka, as the marketing authority, is that it conducts a non-interventional post-authorisation safety study (PASS) to investigate the risks of liver toxicity, basal cell carcinoma and glaucoma associated with use of Jinarc, and to capture information on pregnancy outcomes in Jinarc patients, and also patterns of drug use – in particular off-label use and use in patients over 50 years old – and adverse drug reactions associated with long term use of the drug.3 Measuring the effectiveness of aRMMs is also necessary, to establish whether each of the “special” risk minimisation interventions has been effective or not, and if not why not and what corrective actions are necessary.4
Post-market surveillance of medical devices
Medical devices bring their own safety challenges, including: technical complexity, operator misinterpretation, and device variability or inconsistency. In Europe, their route to market is also significantly different to that of medicinal products. Devices are certified – “CE marked” – for market use by private, Notified Bodies (NBs) operating on a commercial basis. The work of NBs is overseen by the Competent Authority (CA) in each EU member state. NBs certify a device according to European Commission directives which specify standards for manufacturing, expected performance, safety profiles and labelling and responsibilities for adverse event reporting5. However, it is the CAs who have primary responsibility for PS. Although NBs may provide guidance for a PS during their review of a medical device, European Commission directives do not provide authority for CAs or NBs to insist on post-approval studies. There is no clear evidence that PS studies or the set-up of device-use registries6; there is no requirement to formally publicise conducted PS studies, or the compilation of a registry, making it difficult to assess how much post market authorisation activity goes on in practice.7
After complications, such as with PIP breast implants and some metal-on-metal hip replacements, the EU Commission urged member states to tighten controls and improve surveillance of medical devices in the market. It achieved this in part with the MEDDEV guidance documents8, and the journey of bringing the regulations up-to-date had already begun in 2012. Today’s technology and science have outpaced the existing EU legislation drafted in the 1990s, as in contrast to most devices in the 1970s, newer products – ranging from permanent implants to home-use diagnostic devices – can potentially pose greater risks to patients. Other factors driving the revision of the legislation include:
- Consistency: EU Member States’ interpretation and implementation of the current rules is variable between member countries, which may result in different levels of patient and public health protection in the EU.
- Traceability: The ability to trace a medical device to the supplier, ensuring a quicker response to safety concerns, particularly if a product recall is required.
- Transparency: Providing healthcare professionals and patients with information on how medical devices have been assessed for their fitness to be in the market and what clinical evidence there is to show they are safe and effective. The aim is to extend the existing Eudamed9 database of device issues and to make non-confidential information publicly available.
Critically, there will be reinforcement of rules and data for the continuous post-market assessment of medical devices. Post-market clinical follow-up may be performed on a device following marketing approval, which is intended to answer specific questions relating to clinical safety or performance (residual risks) of a device when used in accordance with its approved labelling. This can be viewed as equivalent to the post-authorisation safety study (PASS) for a drug. A post-authorisation safety PASS is carried out after it has been authorised, to obtain further information on its safety, or to measure the effectiveness of any implemented risk-management measures.
Comparing apples with pears?
Drug regulation is a much older discipline than device regulation, and any legislation on device regulation came into being only in the 1990s. Yet in the past decade, the number and complexity of medical devices has exploded. In contrast to most devices in the 1970s, these newer products pose substantially greater risks, even life-threatening, to patients. For example, many new medical devices are permanently implanted in a patient’s body and can be moved or changed, if at all, only with great risk to the patient.
- Cushion, M & Huckle, R. “The Challenges of Implementing Non-interventional Studies in the EU”. Journal for Clinical Studies, Vol 7, Issue 4, pp32-35 (2015).
- Patch C, Charlton J et al. “Use of antihypertensive medications and mortality of patients with autosomal dominant polycystic kidney disease: a population-based study”. American Journal of Kidney Disease. 2011;57(6):856-862.
- European Medicines Agency. “Assessment Report Jinarc International Non-proprietary Name: Tolvaptan”. EMA/154879/2015, 26 February, 2015.
- Guideline on good pharmacovigilance practices (GVP) Module XVI – Risk minimisation measures: selection of tools and effectiveness indicators EMA/204715/2012 Rev 1, 15 April 2014.
- Harmful occurrences, problems or incidents involving medical devices.
- Used in post-market surveillance, Registries are typically extensive data repositories related to patients with a specific diagnosis, condition, or procedure which necessitates using a particular medical device.
- Kramer DB, Tan YT, Sato C, & Kesselheim AS. Postmarket Surveillance of Medical Devices: A Comparison of Strategies in the US, EU, Japan and China. PLOS Medicine. Volume 10, Issue 9, September 2013.
- MEDDEV Guidance’s http://ec.europa.eu/growth/sectors/medical-devices/guidance/index_en.htm
- Eudamed is the European Databank on Medical Devices, in which CAs provide secure information about medical devices, including CE certificates issued, refused or withdrawn.