Drug-Device Combination Products

Organizers and moderators: Tom Sam & Steven Koepke

The exciting world of drug-device products

challenges in a global environment Dr Tom Sam, Merck Sharp & Dohme

The regulatory landscape of drug-device

combination products Dr Ashley Boam, FDA

Challenges of developing drug-device

products in the cardio arena Dr Steven R. Koepke, SRK Consulting, LLC

Transdermal and topical drug delivery by

iontophoresis and other device-mediated processes Dr Ravi S. Harapanhalli, PAREXEL International

The exciting world of drug-device products

Tom Sam Head Global CMC Regulatory Affairs Merck Sharp & Dohme Oss, the Netherlands

AAPS meeting 2011, Washington

My Career ..

Implanon NXT

fun excitement

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The revolution in healthcare

With healthcare technologies - genomics - proteomics, - biotherapies starting to mature and many others being initiated - nano-medicine - personalized healthcare - translational medicine - stem cell therapies technological innovation in the form of medical devices will revolutionize diagnosis and treatment.

Technological Innovation

Ascher Shmulewitz & Robert Langer Nature Biotechnology 24, 277 - 280 (2006)

The revolution in healthcare (2)

Medical devices and drug-device products will be part of the

revolution in healthcare.
Electronics and communications will be integrated into these devices,

allowing the processing and analysis of vast amounts of data in near real-time.
In the near future environment information will be used to

- manage medication, - monitor patient compliance and to - modify treatments in response to diagnostics.
Increasingly, these devices will provide

patient coaching, education and stimulus.

The revolution in healthcare (3)

Demands for in-vitro diagnostics and medical devices will be driven by

the: - value-for-money evaluation of product/ treatment on a patient-by-patient basis, - the increasing integration of electronics and communication and - the move towards diagnostic test kits and medical devices directly linked to individual health portals. Drugs combined with medical devices or as single integral products will provide exciting ways to enhance efficacy and safety of these drugs beyond what could be achieved without these devices.

Examples of Merck Medical Devices

An array of devices, medical devices, combination products and single integral products

DR. SCHOLL'S Custom Fit Orthotic Centers

Fast Company Magazine recognized Merck "for developing a groundbreaking Footmapping Technology for its Dr. Scholl's brand that uses 2,000 pressure sensors to measure the different areas of the foot that take the biggest hits when walking, and then recommends different orthotics solutions."

More background on medical devices

 Similar or even identical systems can be regulated differently in

various regions and countries.

The regulatory implications can be huge ! Examples:

- medicine / packaging - cosmetic - device - medical device (still different risk classes) - combination product - components - accessories - single integral products, etc.

The Regulatory Landscape for medical devices is different from that of pharmaceuticals

Different Regulatory Pathways

Medical Device
EU EU

Medicinal Product
Submission to Competent Authority: - National - Mutual Recognition - Decentralised Procedure Submission to EMA: - Centralised Procedure

CE marking submission to Notified Body

US

US

Submission to FDA/CDRH: - Pre-market Notification (510k) - Pre-market Approval Application (PMA)

Submission to FDA/CBER: - Biologic License Application (BLA) Submission to FDA/CDER: - New Drug Application (NDA)

Pharmaceutical Products and Medical Devices differ in legislation and terminology

Pharma:
Market authorization (approval) Registration file (CTD) Guidelines International Conference on Harmonization (ICH) GMP GCP Pharmacovigilance Post Marketing Surveillance Patient Patient Leaflet

Medical Devices:
Certificate by the Manufacturer / /..etc. Technical documentation (STED) Standards, MEDDEVs Global Harmonization Task Force (GHTF) ISO 13485:2003 / CFR 820.20 ISO 14155:2009 Market Surveillance Vigilance User Instructions For Use

What are the major challenges for pharmaceutical companies when dealing with medical devices?

1. 2.

Obtain an in-depth understanding of the regulatory environment (EU / US / MOW) Learn how to
classify medical devices follow conformity assessment routes leading to CE marking work with the Health Authorities / Notified Bodies adhere to the Essential Requirements use Quality Risk Management throughout the product lifecycle obtain Clinical Evidence develop and maintain the Technical Documentation / STED use the Quality Management System suitable for medical devices fulfill the requirements for post-market surveillance as part of life cycle management Make suitable Quality Agreements

Regulatory environment
The Medical Device Directives regulate the placing on the market and

putting into service of medical devices: Active implantable Medical Device Directive (AIMDD) 90/385 EEC, 1st January 1995 Medical Device Directive (MDD) 93/42/EEC, 13th June 1998 In Vitro Diagnostic Devices (IVD) 98/79/EC, 7th December 2003.

According to the European Directives it is necessary to carry out a

CE-marking process for each Medical Device showing conformity with the European Directive and the Essential Requirements therein.

Drug-device combinations
In deciding how a drug-device combination is to be regulated, it is the

intended mode of action of the combination that is critical.

For a drug-device combination with a medicine or drug providing an

ancillary action, the medicine or drug used must already have regulatory approval for use in that particular application and intended use.
Examples of medical devices that incorporate

medicines and are regulated as medical devices are - catheters with anticoagulant coatings, - drug eluting coronary stents and - antiseptic wound dressings.
Examples of medicinal products that

incorporate an ancillary medical device are - pre-filled syringes, - nicotine patches and - contraceptive implants.

 A medical device designed to administer a drug is only regulated as a

medicinal product when the drug is incorporated or contained within the device for later release.
The device part of a drug-device combination that is regulated as a

medicinal product, must still meet the requirements of the Medical Devices Directive, but CE marking is not applied.

Classification

CLASSIFICATION

NOTIFIED BODY
A Notified Body is a certification organisation

which the national authority (the Competent Authority) at a Member State designates to carry out one or more of the conformity assessment procedures described in the annexes of the Directives.
The Medicines and Healthcare products

Regulatory Agency (MHRA) is the UK Competent Authority under the 3 Medical Devices Directives.
A Notified Body must be qualified to perform

all the functions set out in any annex for which it is designated. The designation may be restricted to specified types of devices and/or Annexes.

CE marking (1)
A CE mark is given by a Notified Body to a medical device once

it has been assessed that the device is conform the Medical Device Directive.
Class I devices are self certified Conformance to the MDD is demonstrated by showing

conformance to the applicable standards.

Which standards are applicable can be evaluated when filling in

the checklist in the MDD on the Essential Requirements.

CE marking (2)
All EU Member States

accept CE marked devices and can CE mark devices for circulation in the EU.
Mutual Recognition

Agreements are being, or have been, negotiated with Switzerland, Australia, New Zealand, USA and Canada.
Turkey, Croatia and

Macedonia are candidate countries to join the EU; they also accept CE marked devices.

ESSENTIAL REQUIREMENTS (1)

Article 3 of the Medical Device Directive states:

'the device must meet the Essential Requirements set out in Annex 1 which apply to them, taking into account the intended purpose of the device concerned'.
Within the EU, meeting the Essential Requirements is

necessary when registering the product with an appointed EU representative registered with a Competent Authority or the Competent Authority itself.
Once a product has been successfully classified as a

medical device, compliance with these requirements, by definition, is essential.

E S S E N T IA L R ESSENTIAL REQUIREMENTS E Q U I R E M E N T S (2) Requirements regarding design and construction: Safety of materials including: toxicity flammability animal origin compatibility biological tissues, cells and bodily fluids medicinal products Sterilising methods and suitability Use of sterile products and conditions of use Safety of devices that are connected to an energy source Mechanical, electrical, electromagnetic and devices that radioactive safety Accuracy of devices with measuring functions Labelling and information supplied with a device Specific requirements for instructions for use.

Design and Development

CLINICAL EVIDENCE (1)

Clinical evidence
must be provided to support the use of a

medical device in humans (MDD).

can be either the results of

- a clinical investigation, - a review of relevant clinical literature or - a combination of both.

MEDDED 2.7.1 provides guidance on when clinical

investigations are appropriate and the requirements for each of the routes.

CLINICAL EVIDENCE (2)

Factors that should be considered are:
frequency of use (if designed to be used repeatedly e.g.

external drug delivery system)

exposure to cycles of use followed by cleaning, followed by

repeated use (if designed to be re-used on separate multiple occasions e.g. as part of a surgical procedure)
lifespan of e.g., implantable devices.

Non-clinical data on e.g. 'wear testing' can be taken into account, but ultimately clinical use and in vivo testing can provide more reliable data

POST MARKET SURVEILLANCE

Medical Device Post-Marketing Surveillance comprises of a

broader scope of activities than vigilance alone.

Manufacturers are required to

gather, compile and monitor post-marketing information about the device derived from various sources, including - customers and users, - market feedback, - competitor product information, - published literature.
Appropriate effective actions must be taken to ensure product safety. The updated MEDDEV guidance reflects the heightened importance of

post marketing surveillance, and the efforts underway to broaden the scope and awareness of device safety information on a global basis.

Continual improvement
Implanon Implanon NXT
X-ray visible, new applicator and new lidding

Triad Group issues a voluntary nationwide recall

All lots of alcohol prep pads, alcohol swabs, and alcohol

swabsticks due to potential microbial contamination.

This recall involves those products marked as STERILE as well

as non-sterile products.
This recall has been initiated due to concerns from a customer

about potential contamination of the products with an objectionable organism, namely Bacillus cereus.
Third parties: Cardinal Health,

PSS Select, VersaPro, Boca/ Ultilet, Moore Medical, Walgreens, CVS, Conzellin
January 5, 2011

A look into the future .

MicroCHIPS starts first clinical trial in humans (03/02/2011)

MicroCHIPS, an offshoot of the Massachusetts Institute of Technology (MIT), created a device which holds small drug doses inside reservoirs that can be opened remotely by dissolving a seal of platinum and titanium. The system will now be used to deliver the Eli Lilly drug Forteo to patients suffering from severe osteoporosis. If the trial is successful, MicroCHIPS hopes the device could be used for as long as a year at a time, meaning patients no longer need to travel to hospitals to receive injections.

Mendor and Novartis develop treatment for diabetes

Finnish company Mendor has begun collaborating

with the Finnish branch of one of the worlds leading medical companies, Novartis. The companies have started up a pilot project, the aim of which is to develop more targeted care for those suffering from Type 2 diabetes. Taking part in the pilot project will be 12 Helsinki clinics as well as 500 Finnish patients with Type 2 diabetes.
All patients will receive common directions to time their blood

glucose measurements, but the timing will nonetheless follow the individuals daily routines. The medical staff will then get an indication of how the blood glucose behaves and evaluate the different treatment options.

FDA Drafts Guidance on Mobile Medical Apps

@HIMSS Prenatal care app AirStrip OB for iPhone

Physicians can use mobile phones to calculate prescription dosages, review disease treatment guidelines, and expliain diagnoses and procedures to patients. The FDA expects that by 2015, 500 million smartphone users will rely on health care apps.

Conclusion
When medicine meets technology new combinations are formed, that
provide new exciting solutions to users; pose different/extra requirements to development

(design control with more emphasis on risk assessment);

are subject to other regulatory and Quality Management

System requirements (ISO, MDD, CFR)

should be maintained actively throughout their product life

based upon post-market surveillance