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Regulatory Intelligence in the Development of OTC Products
Wissenschaftliche Prüfungsarbeit
Scientific Thesis
zur Erlangung des Titels
to obtain the degree
„Master of Drug Regulatory Affairs“
der Mathematisch-Naturwissenschaftlichen Fakultät
der Rheinischen Friedrich-Wilhelms-Universität Bonn
at the Faculty of Mathematics and Natural Sciences,
Rhenish Friedrich-Wilhelms - University Bonn (Germany)
vorgelegt von
submitted by
Kolmal Musa
aus Köln
from Cologne
Bonn 2014
II
Betreuer und 1. Referent: Prof. Burkhard Sträter
Supervisor and 1st Assessor:
Zweite Referentin: Dr. Rose Schraitle
2nd Assessor:
III
Contents
List of Figures …………………………………………………………………………………….V
List of Boxes…………………………………………………………………………………..…VI
List of Tables……………………………………………………………………………………..VI
Abbreviations……………………………………………………………………………………VII
Contents
1. Introduction .................................................................................................................................... 1
1.1. Background ................................................................................................................................... 1
1.2. Definition of Regulatory Intelligence (RI) .................................................................................... 2
1.3. Aim ................................................................................................................................................ 2
1.4. Methodology ................................................................................................................................. 2
1.5. Discussion and Conclusion............................................................................................................ 3
2. Regulatory Framework for OTC medicinal products in the European Union ............................... 4
2.1. Medicinal Product Status ............................................................................................................... 4
2.1.1. Prescription Medicine (Rx) ............................................................................................................ 4
2.1.2. Nonprescription Medicine (OTC) .................................................................................................. 6
2.2. Switching from prescription-only to non-prescription status ......................................................... 8
2.2.1. Criteria for determining the legal status ......................................................................................... 8
2.2.2. Brief Definition of Rx-to-OTC Switch .......................................................................................... 9
2.2.3. The Rationale for Rx-to-OTC switches ......................................................................................... 9
2.2.4. General benefits of switches ........................................................................................................ 11
2.2.5. Regulatory framework ................................................................................................................. 11
2.2.6. Notable Rx-to-OTC Switches worldwide .................................................................................... 12
2.2.7. General Switch Requirements ...................................................................................................... 14
2.2.8. Country conditions for switching ................................................................................................. 16
2.2.9. The Regulatory Classification System ......................................................................................... 16
2.3. Regulatory Criteria for Switching from Prescription-only to Non- prescription Status .............. 17
2.4. Marketing Authorisation Approval Procedures ........................................................................... 19
2.4.1. Type of Marketing Authorisation Applications ........................................................................... 19
2.4.2. Types of MA Approval Procedure for MP .................................................................................. 21
IV
3. Impact of regulatory approval procedure on future regulatory status of medicinal products ...... 25
3.1. Case study-Pantozol® .................................................................................................................. 25
3.2. Case study-Vaprino® ................................................................................................................... 29
3.3. Case study-Viagra® ..................................................................................................................... 32
4. Sources and methods for monitoring and analysis to achieve regulatory competitiveness ......... 35
4.1. Monitoring and analysis of the legal framework and constantly changing regulatory landscape 35
4.1.1. Directives, regulations, guidelines: Impact on OTC status at an European and national level .... 36
4.1.2. Market analysis: Regulatory climate and developments regarding OTC status within various EU
member states............................................................................................................................... 42
4.2. Monitoring and analysis of Competitor activities ........................................................................ 43
4.3. Discussion and Conclusion .......................................................................................................... 46
4.3.1. Discussion .................................................................................................................................... 46
4.3.2. Conclusion ................................................................................................................................... 48
4.4. Data Transparency ....................................................................................................................... 48
4.4.1. Freedom of Information Act ........................................................................................................ 48
4.4.2. European Transparency Policy .................................................................................................... 49
4.4.2.1. Possible sources for Regulatory and competitive intelligence data ............................................. 50
4.4.2.1.1. Transparency Sources on European level .................................................................................... 51
4.4.2.1.2. Transparency Sources on a National level –Germany ................................................................. 55
4.5. Consequences of potential Transparency ..................................................................................... 56
5. Overall Summary ......................................................................................................................... 58
6. Conclusions and Recommendations ............................................................................................ 60
7. References .................................................................................................................................... 62
V
List of Figures
Figure 1: Graphic adopted from The Value of OTC Medicines, Pfizer, The Value of Medicines
(www.pfizer.com/valueofmeds). ................................................................................................................... 8
Figure 2: Graphic adopted from GBI Research, Published April 2012. ...................................................... 10
Figure 3: Graphic adopted from The Value of OTC Medicines, Pfizer, The Value of Medicines
(www.pfizer.com/valueofmeds). ................................................................................................................. 11
Figure 4: Overview of a few “Regulatory Intelligence” involved disciplines. ............................................ 43
Figure 5: Overview of “Regulatory Intelligence” involved disciplines. ..................................................... 46
Figure 6: Overview of “Regulatory Intelligence” involved disciplines and their interactions. ................... 47
VI
List of Boxes
Box 1: Some examples of worldwide switches ........................................................................................... 13
Box 2: Guidelines on switch-related regulations from European Union and UK ....................................... 15
Box 3: Fulfillment of regulatory switch criteria: toxicology, clinical pharmacology and epidemiology ... 18
Box 4: DeLap’s “Switch Principles” ........................................................................................................... 19
Box 5: Eligibility – Mandatory Scope ......................................................................................................... 22
Box 6: Eligibility – Optional Scope ............................................................................................................ 24
List of Tables
Table 1: Overview of Marketing Authorisation Application Types and their legal basis in EU countries . 20
Table 2: Overview on Regulatory Associations - EU/US ........................................................................... 41
Table 3: Overview on Regulatory Networks- EU/US ................................................................................ 42
Table 4: Overview of Clinical Trial-Registry ............................................................................................. 54
VII
Abbreviations
ABDA Arzneibüro Bundesvereinigung Deutscher Apothekerverbände
ADR Adverse Drug Reaction
AE Adverse Event
AESGP Association of the European Self-Medication Industry
Afssaps L’Agence française de sécurité sanitaire des produits de santé
AMVV Ordinance on Prescription-Only Medicinal Products (Arzneimittelverschreibungs-
Verordnung)
AMIS Arzneimittelinformationssystem
ANDA New Drug Application
ATC Anatomic, therapeutic chemical classification
BfArM Bundesinstitut für Arzneimittel und Medizinprodukte
BGBI Bundesgesetzblatt
CAs Competent Authorities
CADREAC Collaboration Agreement between Drug Regulatory Agencies in EU Associated Countries
CDER Center for Drug Evaluation and Research (US FDA)
CHPA Consumer Healthcare Products Association
CHMP Committee for Medicinal Products for Human Use
CMC Quality, Control, Manufacture
CMS Concerned Member State
CPMP Committee for Proprietary Medicinal Products
CTD Common Technical Document
DCP Decentralised Procedure
DGRA Deutsche Gesellschaft für Regulatory Affairs
DIA Drug Information Association (US)
DIMDI Deutsches Institut für Medizinische Dokumentation und Information (Germany)
DPI Dry Powder Inhaler
DGRA Deutsche Gesellschaft für Regulatory Affairs
(D)RA (Drug) Regulatory Affairs
ED Erictile Dysfunction
EFTA European Free Trade Association
EMC Electronic medicines compendium
EMA European Medicines Agency
VIII
EFPIA European Federation of Pharmaceutical Industries and Associations
EPAR European Public Assessment Report
EphMRA European Pharmaceutical Market Research Association
FDA Food and Drug Administration
FDAMA Food and Drug Modernisation Act
FDC&A Federal Food, Drug and Cosmetic Act
FOI Freedom of Information
GORD Gastro-Oesophageal Reflux Disease
GxP Good Practice in different areas (symbolised by the x)
HA Health Authority
IFPMA International Federation of Pharmaceutical Manufacturers Association
ICH International Conference on Harmonisation of Technical Requirements
IMS Institute for Medical Statistics
IND Investigational New Drug Application
INN International non-proprietary name
ISE Integrated Summary of Efficacy
ISS Integrated Summary of Safety
JPMA Japanese Pharmaceutical Manufacturers Association
MA Marketing authorisation
MHLW Ministry of Health, Labour and Welfare
MPA Medical Products Agency
MP Medicinal Product
MRI Mutual Recognition Index
MRP/DCP Mutual Recognition Procedure/Decentralised Procedure
NDA New Drug Application
NIHS National Institute of Health Service
NME New Medical Entity
NIHS National Institute of Health Service
NP National Procedure
NPV Net Present Value
NTA Notice to Applicants
NSAID non-steroidal anti-inflammatory compounds
OPSR Organisation for Pharmaceutical Safety and Research
OTC Over-The-Counter
IX
PDR Physician’s Desk Reference
PhRMA Pharmaceutical Research and Manufacturers of America
PDUFA Prescription Drug User Fee Act
PERF Pan European Regulatory Forum
PI Package Insert
PIL Patient Information Leaflet
PPI Proton pump inhibitor
PMSB Pharmaceutical and Medical Safety Bureau
PSUR Periodic Safety Update Report
PMDEC Pharmaceuticals and Medical Devices Evaluation Center
RA Regulatory Affairs
RAJ Regulatory Affairs Journal
RI Regulatory Intelligence
RMS RMS Reference Member State
ROI Return-on-Investment
Rx “Medicinal Product subject to Prescription-Only-Medicine”
SBA Summary Basis of Approval
SmPC Summary Product Characteristics
SPC Supplementary Protection Certificate
SNDA Supplemental New Drug Application
URL Uniform Resource Locater
USA United States of America
tid ter in die (three times a day)
VFA Verband forschender Arzneimittelhersteller
WHO World Health Organisation
WSMI The World Self-Medication Industry
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1. Introduction
1.1.Background
The scope of regulatory intelligence(RI) encompasses multiple sources; monitoring the
regulatory landscape/environment; RI-Databases; and other regulatory sources to research
questions on regulatory issues such as analysing, discussing of possible procedure types as well
as its implementation in compliance with agency’s requirements inclusively awareness of
advantages/ disadvantages of each single choice of procedure type selected.
The regulatory world is a living and evolving body. Therefore, it is crucial to understand the
necessity of monitoring the regulatory environment and agencies' requirements as result of this
evolutionary process.
RI provides the Regulatory Professional with Information to identify opportunities such as
broader indications; roadmap to product approval; identify possible hurdles e.g. compliance
issues; change in requirements for certain indication. In addition, RI helps Regulatory
Professionals to predict Agency approval requirements as well as its review times.
The consequence of monitoring and gathering of RI will be finally the development of a
regulatory strategy which leads to generate valuable advantages such as decrease in approval
time, reduce of costs of drug development based on current information as well as maximizing of
the target market(s).
For a global regulatory strategy, there is a necessity to keep abreast of worldwide regulatory
information as a change in the global landscape can affect the global regulatory strategy in terms
of pharmaceutical development, planning for the implementation of the Global Regulatory
Strategy across multiple regions as well as identifying of development areas requiring special
considerations across various regions. Consequently this might result in achieving a widening of
market corridors and thus serve the best commercialization of both newly and existing developed
products.
Finally, as RI can identify competitive advantages in an increasingly complex regulatory
landscape for the global development of drugs and so determine the regulatory pathway, a
successfully implemented RI process can be considered as a powerful business driver.
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RI can promote product lifecycle with regard to procedural, technical, scientific and strategic
input. Key roles include general information gathering and tracking legislation, followed by
information dissemination and utilization. For this purpose, identification and utilization of
appropriate relevant information sources for gathering of respective data with reliable updates of
the latter are of importance.
1.2.Definition of Regulatory Intelligence (RI)
Regarding to the different languages in the European Union and EEA, the word 'intelligence' may
vary in its interpretation within the European countries. There are different definitions for
'regulatory intelligence' (RI). However, relying upon the English language and in accordance with
the standard dictionary “Oxford English Dictionary” can give a further definition for RI.
However, two Regulatory Intelligence Network Groups (RINGs) in association with the Drug
Information Association (DIA) have proposed the following definition:
RI is defined as “the act of gathering and analyzing publicly available regulatory information.
This includes communicating the implications of that information, and monitoring the current
regulatory environment for opportunities to shape future regulations, guidance, policy, and
legislation” (Regulatory Intelligence Working Group, Regulatory Intelligence, 2010).
1.3.Aim
Based on a description of the regulatory framework of Medicinal Products in the EU, this thesis
examines possibilities to successfully implement Regulatory Intelligence in the development of
an adequate regulatory strategy for the authorization of a medicinal product (MP) as OTC. In this
Thesis the focus is on already authorised pharmaceutical products.
1.4.Methodology
The scope of regulatory intelligence encompasses multiple sources; monitoring the regulatory
landscape/environment; RI-Databases; and other regulatory sources to research questions on
regulatory issues such as analysing, discussing of possible procedure choices as well as its
implementation in compliance with agency’s requirements inclusively the advantages/
disadvantages of each single choice.
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The Methodology applied in this thesis includes two kinds of research online research and
internal research.
Online Research
• Research and/or Monitoring
o Primary Research in e.g. pharmaceutical industry, regulatory affairs, business
development, Licensing and R&D, government health ministries and regulatory agencies,
as well as other relevant regulatory sources such as groups and associations, etc.
o Secondary Research such as patent searching, trade journals, annual reports and other
company’s literature, published regulatory agency materials, etc.
Internal research
• Qualitative Research
o Preparation of department specific questions and common questions as well- regarding to-
not only gathering information on competitor companies- but also tracking and update of
these as well as its communication within the company
o Performance of interviews with employees of different disciplines
o Carrying out analyzes of the interview research results
1.5. Discussion and Conclusion
Discussion
Various involved departments provide an analysis and interpretation of gathered information
based on different applied tools in the context of interpretation and analysis as well as various
regulatory sources in order to serve strategy decisive measurements of events and/or activities
such as the
• Forecasting of regulatory activities of specific competitors for e.g. its life cycle management
and/or future strategies such as Rx-to-OTC switch, and medicinal product to medical device
or to Cosmetics
• Grading of possible concerns
Communication and/or notification of each department to Regulatory Affairs department
• To better and early prepare for a strategy in the market(s) analysed
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• Preparing for new switch strategy
• Strategic planning.
Conclusion
In this thesis based on the results generated from the applied methodology show that the
communication and/or dissemination of gathered data between the departments plays a crucial
role in the development of a company future strategy! As the notification of each department to
Regulatory Affairs department aims at to better and early prepare for a strategy in the market(s)
analysed e.g. preparing for a new switch strategy.
However, consequently the communication between all involved disciplines has become a
necessary part of business models for research-driven pharmaceutical companies.
2. Regulatory Framework for OTC medicinal products in the European Union
2.1. Medicinal Product Status
Legal status of a medicinal product is “the conditions and restrictions under which the medicinal
product should be made available to patients”. According to the pharmaceutical legislation,
Regulation (EC) No 726/2004, when the Committee for Medicinal Products for Human Use
(CHMP) gives its opinion of granting a marketing authorization to a Medicinal product, the legal
status must be annexed to that opinion. This is required by the Regulation (EC) No 726/2004.
The Documents annexed to CHMP’s favorable opinion to the granting of marketing authorization
and according to Article 9(4) (b) of Regulation (EC) No 726/2004, shall include “details of any
conditions or restrictions which should be imposed on the supply or use of the medicinal product
concerned, including the conditions under which the medicinal product may be made available to
patients, in accordance with the criteria laid down in Title VI of Directive 2001/83/EC, as
amended” (EMEA, Regulation (EC) No 726/2004) (EMA, Regulation (EC) No 726/2004).
2.1.1. Prescription Medicine (Rx)
Prescription medicine is an authorized medicine that is regulated by legislation to require a
medical prescription before it is available to patients.
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"Rx" is often used as a short form for prescription drug in North America. It is an abbreviation
for the Latin "recipe", an imperative form of "recipere", meaning "take" (Crane, 2014). Criteria
for classifying a medicinal product as subject to medical prescription are stated in Article 71 of
Directive 2001/83/EC. Thus, when a medicinal product fulfills these criteria is a subject to a
medical prescription. Based on Article 72, a medicinal product which does not meet these criteria
is not subject to a medical prescription.
According to Article 71 of Directive 2001/83/EC that “medicinal products shall be subject to
medical prescription where they:
• are likely to present a danger either directly or indirectly, even when used correctly, if utilised
without medical supervision, or
• are frequently and to a very wide extent used incorrectly, and as a result are likely to present
a direct or indirect danger to human health, or
• contain substances or preparations thereof, the activity and/or adverse reactions of which
require further investigation, or
• are normally prescribed by a doctor to be administered parentally.
This is according to the new template for Guidelines (EMA/CHMP, 2006).
These criteria including the determination if their application for a specific medicinal product or
not are further detailed in part one of the “Guideline on changing the classification for the supply
of a medicinal product for human use”.
Medicinal products which do meet the criteria listed in Article 71, and in accordance with Article
72 of Directive 2001/83/EC, as amended, are considered to be subject to medical prescription.
In accordance with Article 71(4) in case if a medicinal product, which doesn’t meet any of these
criteria for supply based on medical prescription, may be classified for supply without medical
prescription, if:
“the maximum single dose, the maximum daily dose, the strength, the pharmaceutical form,
certain types of packaging and/or other circumstances of use, can make supply without medical
prescription appropriate.” In most instances, a novel medicinal product for which a marketing
authorization application has been submitted to the EMA via centralized procedure, DCP/MRP
and/or via national procedure to the competent authority (CA) for granting a marketing
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authorization will be subject to medical prescription according to Article 71 of Directive
2001/83/EC, as amended.
The Annex to the “The guideline on Legal Status for the Supply to the Patient of Centrally
Approved Medicinal Products” provides the summary of category levels (EMA/CHMP, 2006).
2.1.2. Nonprescription Medicine (OTC)
Over-the-counter (OTC) drugs are medicines not prescribed by a healthcare professional, sold
directly to a consumer, as compared to prescription drugs that can be sold only to consumers on a
valid prescription.
CHPA defines OTC as – A drug product that can be used safely and effectively for the labeled
indication, based on the label alone, without the involvement of a medical professional
(Consumer Healthcare Products Association (CHAP), 2014).
In general, drugs are classified as nonprescription (OTC) drugs, if they are estimated to be used
safely and effectively without medical supervision.
The basic requirements for self-medications are the following:
• medicines must be of proven safety, quality and efficacy
• medicines are indicated for conditions that can easily be recognized by the consumer/patient
himself
• Patients have the support of good quality of information supplied with medicines and access
to health care advice from professionals such as pharmacists to provide a carefully and safely
use of medicines according to package information leaflet (PIL).
The classification of the medicines is regulated by active pharmaceutical ingredients (APIs) and
not finished products.
Regulations detailing the establishments where nonprescription drugs may be sold, who is
authorized to dispense them, and whether a prescription is required vary considerably from
country to country.
The health care system within the EU gained a high value of self-medication and still increasing.
Reasons behind this could be the clear advantages of self-medication in terms of associated lower
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costs and less time consume especially when consumers/patients may not feel it is necessary to
have an appointment with health care professionals. However, health care professionals,
governments and self-medication suppliers are challenged as they have to be aware of the
necessity of having a self-medication adequate framework in place.
A significant problem of people treating themselves with prescription drugs is declined by wider
availability of nonprescription medicines especially in countries where enforcement of the
prescription requirement is insufficient. A study in Mexico showed a 20% decrease in the degree
of self-prescription in the 10 years between 1989 and 1999. This was attributed to the significant
number of switches authorised by the Mexican Ministry of Health between 1995 and 1998
(Bolaños, 2005).
This observation is supported by the statement in the World Health Organization’s (WHO)
principal guidelines on nonprescription medicines: “… in some countries a large number of
medicinal products originally intended primarily for use under medical supervision are in fact
widely sold without prescription. In such instances, recognition of the real self-medication
situation and the introduction of appropriate safeguards (e.g. adapted package sizes and texts)
may be more in the public health interest than the maintenance of a merely theoretical
prescription status. The possibility of considering the reclassification of products to non-
prescription status on the basis of experience in other countries should be borne in mind”
(Association of the European Self-Medication Industry (AESGP), 2000). As a matter of fact, in
the United States, for example, Rx-to-OTC switch products accounted for about 50% of all OTC
sales with some of them building up a completely new self-medication category previously not
available to consumers (e.g., smoking cessation aids or treatments for hair-growth) (Mahecha
2006), (Figure1). Also, in Europe, eight of the top twenty brands are by now the result of the
product switch (Tisman 2010), (Stäbler, 2013).
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Figure 1: Graphic adopted from The Value of OTC Medicines, Pfizer, The Value of Medicines
(www.pfizer.com/valueofmeds).
Source: Consumer Healthcare Products Association (CHPA). The Value of OTC Medicine to the
United States, January 2012. Retrieved from: http: //www.chpa.org/ValueofOTCMeds2012.aspx.
2.2. Switching from prescription-only to non-prescription status
2.2.1. Criteria for determining the legal status
Levels of categories in relation with the conditions for product supply as well as the criteria for
the establishment of the Legal Status by the competent authorities (CAs) are laid down in Title
VI (i.e. Articles 70 to 75) of Directive 2001/83/EC, as amended (EMA, Directive 2001/83/EC).
Article 70 of Directive 2001/83/EC provides two classifications for the supply of medicinal
products for human use in the Community.
The medicinal product is classified either as subject to medical prescription or not subject to
medical prescription. Information on regulatory criteria as well as “Switch Principles” is
available in subsection 2.3(see also box 3 and 4).
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2.2.2. Brief Definition of Rx-to-OTC Switch
Rx-to-OTC switch refers to the transfer of proven prescription drugs (Rx) to nonprescription, so-
called over-the-counter (OTC) status. Rx-to-OTC switch is a data-driven, scientifically rigorous,
and highly regulated process that allows consumers to have OTC access to a growing range of
medicines.
The United States Department of Food and Drug Administration (FDA) defines Rx-to-OTC
switch as “over-the-counter (OTC) marketing of a drug product that was once a prescription (Rx)
drug for the same indication, with the same strength, dose, duration of use, dosage form,
population, and route of administration” (Mahecha, 2006).
2.2.3. The Rationale for Rx-to-OTC switches
Over-the-counter (OTC) drugs are available on the market without prescription and are widely
used by consumers to treat minor ailments. FDA defines OTC drugs as “drugs that are safe and
effective for use by the general public without seeking treatment by a health professional”.
Today there are over 300,000 OTC medicines and ingredients available for purchase to treat a
broad range of conditions including high cholesterol, weight management, skin disorders and
respiratory infections. OTC medicines are strictly regulated and a number of regulatory processes
have now been established to enable new and approved products to be reviewed and approved in
a clear and transparent manner.
“In light of the complex nature of the prescription to nonprescription reclassification process and
the fact that there are many stakeholders involved, there is certainly no single \one-size-fits-all"
rationale for Rx-to-OTC switches.” (Stäbler, 2013) The driving forces behind switches are pretty
diverse and multifactorial as well as depending on potential benefits implied by a certain switch
for the various stakeholders affected.
Outside the pharmaceutical industry sector the most important intrinsic driving force behind the
Rx-to-OTC switch movement is likely to be embedded in the ever prevailing need for the
implementation of cost-containment measures and the wish to transfer drug distribution costs
from the government to the individual consumer (Bond 2008). Multiple economic analyses of
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Rx-to-OTC switches demonstrated entire cost savings to the health care system by shifting parts
of these costs "from the public purse to the private" (Aronson 2009; Soller 1998; Sullivan 2005).
Historically, the predominant party initiating the switch of a specific ingredient or drug product
from Rx to OTC status has been placed in the ranks of the pharmaceutical industry. In her
analysis of the characteristics of Rx-to-OTC switch processes Mahecha believes that the
motivation of a pharmaceutical manufacturer is mainly based on strategic reasons regarding drug
product sales in the context of life-cycle-management (Figure 2), the defense of generic
competition after expiration of the Rx patent or the enlargement and growth of an OTC drug
portfolio in response to consumer needs and demands for innovative self-medication products
(Gossel 1991; Mahecha 2006; Pawaskar 2007).
In this way, "fostering self-reliance and enhancing consumer choice without compromising the
consumer's safety and economic well-being [should] stand as the guiding values for the switch
evaluation process" (Stitching AESGP Foundation 2002) (Stäbler, 2013).
Figure 2: Graphic adopted from GBI Research, Published April 2012.
11
2.2.4. General benefits of switches
In addition to that people can visit a pharmacy rather than wait for an appointment with their
doctor, they can treat common conditions that have easily recognizable symptoms, such as hay
fever and cold sores, and reduce the time from the onset of symptoms to the treatment as well.
The classic chronic diseases such as diabetes, cardiovascular issues, etc. are not to manage in
most countries on the basis of pure self-medication.
This allows physicians to spend more time on serious health matters which results in having
impact on quality of care. It enables the national health systems to save expenses caused by
illness when employees are absent from work.
Figure 3: Graphic adopted from The Value of OTC Medicines, Pfizer, The Value of Medicines
(www.pfizer.com/valueofmeds).
2.2.5. Regulatory framework
In accordance with Article 74 of Directive 2001/83/EC, as amended, if new facts brought to its
attention, the competent authorities should, where appropriate, change the classification of a
medicine by applying the criteria listed in Article 71 of that Directive.
Article 74a of Directive 2001/83/EC, introduced by Directive 2004/27/EC states that “Where a
change of classification of a medicinal product has been authorized on the basis of significant
preclinical tests or clinical trials, the competent authority shall not refer to the results of those
12
tests or trials when examining an application by another applicant for or holder of marketing
authorization for a change of classification of the same substance for one year after the initial
change was authorized.” Article 54 of EU Directive 2004/27/EC amends Directive 2001/83/EC
wording, inserting a new Article 74 a.
According to Article 74a of Directive 2001/83/EC, a change of classification may benefit from
one year data exclusivity.
‘Data exclusivity’ means that for a defined and limited period a regulatory authority must not
refer to the data of one party to grant registration or approvals for another party, without the
agreement of the owner.
2.2.6. Notable Rx-to-OTC Switches worldwide
According to the reports of the World Self-Medication Industry (WSMI) “In the public health
domain, citizens are increasingly taking greater Control of their own healthcare… they are
becoming more demanding and more pro-active in their choices and becoming advocates of their
own life” (European Commission DG Health and Consumer Protection Future Challenges, Paper
2009-2014). Many prescription-to-nonprescription switches now have a long record of bringing
new self-medication opportunities to people, and a solid track record of safety in use. Older
switches with a long safety record include:
• Acetaminophen / Paracetamol – switched in the 1950’s
• Nasal decongestants and antihistamines – switched in the 1970’s
• Athlete’s foot products – switched in the 1970’s
• Ibuprofen – switched in the 1980’s
• Nicotine Replacement Therapy (NRT) – switched in the 1990’s (The World Self-Medication
Industry (WSMI), 2000)
Improvements in people’s general knowledge, level of education and socioeconomic status in
many countries form a reasonable basis for successful self-medication. New drugs with specific
pharmacological action, such as histamine H2-receptor antagonists, non-steroidal anti-
inflammatory compounds (NSAID) and nicotine preparations for cessation of smoking, have
been successfully reclassified from prescription to non-prescription status in many countries
13
(WHO Guidelines for the Regulatory Assessment of Medicinal Products for use in Self-
Medication” (Association of the European Self-Medication Industry (AESGP), 2000).
In brief, up to now many classes of ingredients have been switched in a variety of countries, with
the authorities in the UK, Germany, Australia and the US taking a lead (Box 1) (The World Self-
Medication Industry (WSMI), 2000).
Box 1: Some examples of worldwide switches
• Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, diclofenac, naproxen.
These can be used for rheumatic pain, migraine, mild to moderate pain and dysmenorrhoea
and sore throats
• Antihistamines such as acrivastine, cetirizine and loratadine for prevention and treatment
of hay fever.
• H2 antagonists such as cimetidine and ranitidine for acid indigestion and heartburn
• Proton pump inhibitors such as omeprazole and pantoprazole for heartburn and acid
indigestion
• Vitamin D3 analogues such as calcipotriol for psoriasis
• Levonorgestrel for emergency hormonal contraception
• Antifungals such as fluconazole for vaginal thrush; amorolfine for nail infections and
terbinafine for athlete’s foot
• Antivirals such as penciclovir and aciclovir for cold sores and oseltamivir for influenza
• Simvastatin for lowering cholesterol and prevention of coronary heart disease
• Triptans for migraine
• Antimicrobials such as chloramphenicol for bacterial conjunctivitis and azithromycin for
chlamydia
• Orlistat for weight management and obesity
Source: The World Self Medication Industry (WSMI).
A comparison of over 200 ingredients and their legal classification status in 37 countries is
provided on the Website of both, WSMI and the Association of European Self-Medication
Industry (AESGP) www.wsmi.org, and www.aesgp.be. The Nonprescription Ingredients
14
Classification Tables are available through WSMI’s website at: http://www.wsmi.org/otc.htm and
the AESGP website at http://www.aesgp.be/publications/otcIngredientTables.asp
The acronym “OTC” means that at least one dosage or form of the ingredient has the legal status
of nonprescription medicine in the country concerned (see also subsection 2.1.2 Nonprescription
medicine” (OTC)).
2.2.7. General Switch Requirements
When deciding on whether a medicinal product can be reclassified to be available as OTC
product, regulatory authorities need to weigh the benefits of its easier access against its potential
harm from unsupervised or inappropriate use. As no medicinal product can be completely safe,
applicants in these countries are required by regulatory authorities to provide appropriate
evidence of a wide margin of safety, along with convincing evidence of effectiveness, before
transferring the product to non-prescription status. The safety profile is determined and
documented in the case of switch products through years of experience and extensive use as a
prescription drug. Issues such as reimbursement status or professional monopolies shouldn't be
subject of an assessment. Also in order to concentrate resources in industry and the authorities, a
clear timetable is necessary as well as clear communication by all parties and agreed action to be
taken to achieve a switch in the desired time frame. In order to avoid unnecessary repetition of
other countries' experiences, International comparison is therefore the important first step for
switching products which have a long history of safe and effective use.
Basically, non-prescription products do not need to be subject to the same extent of regulation as
a new prescription medicine at the point of making a switch application, or in its ongoing usage.
The safety of non-prescription medicines can be optimized by implementing several potential
regulatory strategies such as further reduction of the potential for harm by specifying the
concentration, dose, or pack size that a pharmacist can supply without prescription.
In general, it is important that the evaluation of a product or ingredient be based only on benefit/
risk criteria. The medicinal product should be safe for self- supervision and the condition to be
treated should be self-diagnosable or with a previous diagnosis from their physician for some of
the more complex switches. Furthermore, a clear, transparent and a well-grounded switching
procedure is a basic requirement for successful switch regulation. Box 2 gives details of the
15
specific switch regulations e.g. Germany. In Germany, the procedure for a change of
classification status is clearly defined in the German Medicines Law (AMG). In the last few
years, a considerable number of switches have been recommended by the German Expert
Committee for the Classification of Medicines and subsequently enacted within nine months. The
responsibility to decide on classification lies with the Federal Ministry of Health. Although
applications can in principle be made by anybody, it is usually the manufacturer who initiates a
switch application. In Germany, the procedure for change of classification status is explicitly
defined in the German Medicines Act (AMG).
In recent years, a significant number of switches have been recommended by the German
Technical Committee for the classification of drugs and afterwards approved within nine months.
The Federal Ministry of Health is the decision maker in terms of reclassification of a medicine.
Classification applications can be made by anyone but it is usually made by the manufacturer
who initiates a switch application.
Box 2: Guidelines on switch-related regulations from European Union and UK
Guideline Website
EU
Guideline on changing the
classification for the supply of a
medicinal product for human use
http://ec.europa.eu/enterprise/pharmaceuticals/e
udralex/vol-2/c/switchguide
UK
MHRA Guidance Note 11.
Changing the Legal Classification
in the United Kingdom of a
Medicine for Human Use
http://www.mhra.gov.uk/Howweregulate/Medi
cines/Licensingofmedicines/Legalstatusandrecl
assification/index.htm
Source: The World Self-Medication Industry (WSMI).
16
2.2.8. Country conditions for switching
Switching of drugs status from prescription into non-prescription represents clear opportunities
for countries to improve public health.
There are a number of important basic conditions for switching. These include an appropriate
regulatory classification system, government (political) support, the availability of information
for patients and consumers, assisting health care professionals and the recognition and reward for
the companies developing new switches. Switches, including those which were held to be
inappropriate for non-prescription status in the past, can be used safely and successfully required,
industry, government, pharmacists and physicians work together in order to get the information
and educational support consumers need to make informed decisions for self-care and self-
treatment options.
2.2.9. The Regulatory Classification System
A prerequisite for a change in the status of a medicinal product is the existence of a clear
distinction between prescription and non-prescription medicine at the regulatory level. The
switch of ingredients makes little sense when prescription and non-prescription products are not
differentiated in a market. For example in Spain a new Medicines Law to implement the
provisions of the EU’s 2004 pharmaceutical revision was adopted in 2006 as the Law on the
Guarantees and Rational Use of Medicines.
This above mentioned law distinguished prescription and nonprescription medicines which
resulted in a number of changes to the distribution system for pharmaceuticals. After, the delivery
of prescription medications without a prescription was treated as a serious infringement. As
consequence to this regulation, different ingredients were switched to non- prescription status in
early 2007, including topical ketoconazole, terbinafine, etofenamate, ketoprofen, loratadine,
azelastine, and NRT. There is graduation in the level of availability of nonprescription products.
This is the case e.g. in Australia, New Zealand, Finland, France, Sweden and the UK. There are
some sub-divisions as well in the non-prescription category such as a “behind the counter” class –
where there is a need for pharmacist assistance; pharmacy “self-selection”, or “general sale”
through any retail outlet.
17
Example:
In Australia, a number of athlete’s foot remedies have been switched from schedule S2 (self-
selection in pharmacies) to general sale since 2006.
In Finland, NRT products were moved from pharmacy only to general sale distribution as from
February 2006.
In Sweden, the sale of NRT products was allowed outside of pharmacy as of March 2008. The
term “switch”, may also be used for the reclassification of nonprescription medicines from
“behind the counter” to “general sale” status, in countries where these categories exist.
Apart from the availability of different non-prescription classes within different countries, the
switching procedure differs from country to country. At the basis of the dissimilarities in the
switching procedures for prescription- only to non-prescription medicines in different countries -
i.e., in some countries such as Germany or Finland switches take place ingredient wise, in others
though product wise (e.g. in the UK) - is the governmental leadership as well as the legal and
regulatory framework in individual countries. For example, the USA, China, Japan, Mexico and
the UK have all demonstrated in different ways interest and support for the processes of
switching.
2.3. Regulatory Criteria for Switching from Prescription-only to Non- prescription
Status
“In general, a medicinal product may only be placed on the market in the European Union3 when
a marketing authorization has been issued by the competent authority of a member state for its
own territory (a national authorization) or when an authorization has been granted for the entire
Community (a Community authorization) in accordance with effective legal requirements (i.e.,
Article 6, Directive 2001/83/EC, as amended4, and Article 3, Regulation (EC) No 726/2004).”
(Stäbler, 2013).
As mentioned in subsection 2.2.1, the medicinal product is classified either as subject to medical
prescription or not subject to medical prescription. In order to successfully change a drug's legal
18
status from Rx to OTC, it must fulfill specific criteria. While Box 3 provides a brief overview of
these criteria, Box 4 provides a brief overview of “Switch Principles”.
Box 3: Fulfillment of regulatory switch criteria: toxicology, clinical pharmacology and
epidemiology
Potential safety issues:
• Toxicity:
o carcinogenicity
o reproductive toxicity
o side effects
• Therapeutic hazards:
o misdiagnosis (self-selection, self-diagnosis)
o treatment failure (delayed professional treatment)
o incorrect use (long-term self-monitoring, overdose, misuse)
o drug interactions
Potential effectiveness issues, based on nature/severity of condition:
• Choice of dose, dose interval, age restrictions, etc.
Ability of label to convey core communication objectives
Benefit/Risk assessment
• The benefits of using the product as OTC clearly outweigh the risks
Issues to consider and address by pharmaceutical entrepreneurs when filing an Rx-to-OTC
switch application (based on CHPA 2000).
19
Box 4: DeLap’s “Switch Principles”
Fundamentals:
• Can the condition be adequately self-diagnosed?
• Can the condition be successfully self-treated?
Points to consider:
• Is there a need for physician evaluation of the condition?
• What is the nature and severity of adverse effects of consumer misdiagnosis and delay in
correct diagnosis?
• Regarding effective product use, what is the nature of consumer understanding of product
use?
• What is the consumer understanding of the expected benefit?
• Does the consumer have the ability to assess treatment effect?
Safe product use:
• What is the consumer understanding of product directions for safe use?
• What is the consumer understanding of what to do if the product isn’t working?
• What is the consumer ability to identify adverse effects and the consumer ability to
determine when adverse events may require professional care?
• What is the consumer expectation of safety?
Sources: Switch principles elaborated by Robert DeLap, MD and Director of the Office of
Drug Evaluation V, at the 1998 CHPA Research and Scientific Development Conference (from
Soller 2002) (Stäbler, 2013).
2.4. Marketing Authorisation Approval Procedures
2.4.1. Type of Marketing Authorisation Applications
In accordance with EU Directive 2001/83 and Regulation (EC) No. 726/2004 governing
medicinal products, in order to legally place a medicinal product on the market in the European
Economic Area (EEA), a Marketing Authorisation (MA) or ‘licence’ must first be approved. To
obtain an MA, a Marketing Authoriation Application (MAA) is submitted to the appropriate
Competent Authority(s) (CAs), for assessment and MA approval. According to the Directive
2001/83 and Regulation (EC) No. 726/2004 governing medicinal products, to legally market a
medicinal product on the market in the EU and the European Economic Area (EEA), a Marketing
20
Authorisation (MA) needs first to be granted. In order to obtain a MA, a Marketing Authorisation
Application (MAA) must be submitted to the appropriate competent authority (CA).
Applications extent and content are depending on whether the active substances concerned are
new or existing ones. Applications in case of new active substances are described as “full
application”. Otherwise applications for medicines containing known substances are described as
“abridged applications”. The legal basis for all types of marketing authorisation applications is
set out in Directive 2001/83/EC and Regulation (EC) No 726/2004. The Presentation and Content
of the Common Technical Document (CTD) are described in “Notice To Applicants” Volume 2
B.
Table 1: Overview of Marketing Authorisation Application Types and their legal basis in EU
countries
Application Type Articles of Directive
2001/83/EC
Full applications Article 8(3)
Generic medicines and similar biological medicinal products Article 10
Applications relying on well- established medicinal use
supported by bibliographic literature
Article 10a
Applications for new fixed combination products Article 10b
Applications based on informed consent from a marketing
authorisation holder (MAH) for an authorised medicinal
product
Article 10c
Source: (Die Deutsche Gesellschaft für Regulatory Affairs e.V. (DGRA), 2014).
Generic products
If the new product meets requirements for a generic product defined in Article 10 (2)b of the
Directive 2001/83/EC (as amended), then it can be authorised without its own clinical and pre-
clinical testing data. The data requirements and the assessment process aim to ensure that patients
21
could be switched between the brand leader product and a generic version without causing any
therapeutic problems.
Existing drugs with new forms, routes and indications
Sometimes, although the drug is the same, the new product has a different strength or
pharmaceutical form or is used by a different route or for different clinical uses. In these cases the
company can submit more pre-clinical and clinical data to supplement their abridged application
(The 'Notice to Applicants' refers to these as 'other abridged' applications). The relevant legal
basis is Article 10(3) of Directive 2001/83/EC. The full text of the Notice to Applicants is
available on The European Commission - Enterprise DG - Pharmaceuticals and Cosmetics
website.
Existing drugs in new combinations
New combinations of existing drugs may also be proposed though they may need a full data
package to support them (Article 10b).
2.4.2. Types of MA Approval Procedure for MP
There are several alternative procedures available to market a new Rx or OTC product or to seek
reclassification of a medicinal product from Rx to OTC status (Rx-to-OTC switch). Which
procedure is to be selected, depends on which countries the product is going to be marketed in
and type of medicinal product.
Centralised procedure
In the European Union (EU), a company may submit a single application to the European
Medicines Agency (EMA) for a marketing authorization (previously a product license). A
Marketing authorisation granted via centralised procedure (CP) is valid for the entire EC Market
plus Iceland, Liechtenstein and Norway (The Heads of Medicines Agencies website (HMA),
2014). This is called the centralised (or community) authorisation procedure. While it is
mandatory for certain types of medicines, it is optional for others. The precise scope of the
centralised procedure through which medicinal products must or may be authorised is defined in
Article 3 of Regulation EC/726/2004.
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• “Mandatory” scope of the centralised procedure according to Article 3(1) of the Regulation
EC/726/2004: “1. No medicinal product appearing in the Annex may be placed on the market
within the Community unless a marketing authorisation has been granted by the Community
in accordance with the provisions of this Regulation.” (Directive 2001/83/EC – as amended,
2001). (Box5)
Box 5: Eligibility – Mandatory Scope
1. Medicinal products developed by means of one of the following biotechnological processes:
• Recombinant DNA technology
• Controlled expression of genes coding for biologically active proteins in prokaryotes and
eukaryotes including transformed mammalian cells
• Hybridoma and monoclonal antibody methods
• Similar biological (“biosimilar”) medicinal products, which are developed by one of the
biotechnological processes provided above
2. Advanced therapy medicinal product (ATMP) as defined in Art. 2 of Regulation (EC) No
1394/2007:
• Gene therapy medicinal products
• Somatic cell therapy medicinal products
• Tissue engineered products (TEP)
3. Designated Orphan Medicinal Products according to Regulation (EC) No 141/2000
4. Medicinal products containing a new active substance (NAS), for which the therapeutic
indication is the treatment of any of the following diseases:
• Acquired immune deficiency syndrome (HIV)
• Cancer
• Neurodegenerative disorder (e.g. Alzheimer’s disease, etc.)
• Diabetes
• Auto-immune diseases and other auto-immune dysfunctions
• Viral diseases
5. Clarification on the definitions of the mentioned diseases:
Scientific aspects and working definitions for the mandatory scope of the centralised
procedure [Regulation (EC) No 726/2004 of the European Parliament and of the council of
31 March 2004]
23
Source: Adopted from DGRA, Dr. Baader, 8. - 9. November 2013, Teva Pharma GmbH
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/200
9/10/WC500004085.pdf
Pantoprazole is the first proton pump inhibitor (PPI) that received European wide OTC MA and
is the second OTC product that received approval in the CP after Glaxo Group Limited received
the centralised OTC status in July 2009 from the European Commission for alli 60 mg hard
capsules (with orlistat as active ingredient) (EMA, 2009) (see also Subsection 3.1. Case study
Pantozol®).
• “Optional” scope
Article 3(2) defines the so called “optional” scope of the centralised procedure:
“2. Any medicinal product not appearing in the Annex may be granted a marketing authorisation
by the Community in accordance with the provisions of this Regulation, if:
(a) the medicinal product contains a new active substance which, on the date of entry into force
of this Regulation, was not authorised in the Community; or
(b) the applicant shows that the medicinal product constitutes a significant therapeutic, scientific
or technical innovation or that the granting of authorisation in accordance with this Regulation is
in the interests of patients or animal health at Community level.” (Regulation (EC) No 726/2004
of the European Parliament and of the Council, 2004).
The content of Article 3 (2) paves the way for the central approval of drugs that can be dispensed
without a prescription. The applicant must give in detail why one of the criteria of Article 3 (2)
applies to the OTC product in question. The given justification will be evaluated on a case-by-
case basis by The Committee for Medicinal Products for Human Use (CHMP). Based on the
outcomes of the CHMP evaluation, the European Medicines Agency will notify confirmation of
the eligibility to the centralised procedure. Data exclusivity periods potentially applicable for
approved products by centralized procedure are defined in Article 14 (11) of Regulation
EC/726/2004. Marketing applications submitted before 20 November 2005 receives the former
data exclusivity period of ten Years. Other authorisation procedures are available for medicinal
24
products that do not fall within the mandatory scope of the centralised procedure such as the so
called “National”, “Decentralised”, and “Mutual recognition” Procedures (NP, DCP, MRP)
(Box6).
Box 6: Eligibility – Optional Scope
1. Optional scope (Article 3(2)):
• Innovative medicinal products containing a NAS (Article 3(2)a)
• Medicinal products constituting a significant therapeutic, scientific or technical
innovation as well as medicinal products of interest for patients at Community level
(Article 3(2)b)
2. Generics/hybrids of centralised MAAs (Article 3(3))
3. Duplicate/multiple or informed consent marketing authorisations of centrally authorised
medicinal products
In all cases, eligibility must be requested from the EMA by the Applicant!
Source:
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/
10/WC500004085.pdf. Adopted from DGRA
National Procedure
Each EU Member State has its own procedures for the authorisation, within their own territory, of
medicines that fall outside the scope of the centralised procedure. Information about these
national procedures can normally be found on the website of the national medicine authority in
the country concerned. The EMA home page provides a list of regulatory authorities in the
European Union (EU) and European Economic Area (EEA) that are responsible for human
medicines, e.g. in the UK, this is the MHRA.
Applicants will receive assessment reports for major, standard and complex national initial
applications. The assessment report will be sent to the applicant with the request for further
information at the initial assessment stage. Following the applicant’s submission of responses, a
new assessment report (containing the assessment of the responses only) will be sent to the
applicant. These reports will help applicants better understand the context and basis of the
comments raised by assessors.
25
Decentralised procedure
The decentralised procedure (DCP) may be used to obtain a marketing authorisation in several
Member States when the applicant does not yet have a marketing authorisation in any EU country
and the product does not fall within the mandatory scope of the centralised procedure.
Mutual recognition procedure
In the case of the mutual recognition procedure (MRP), a so called reference member state
(RMS) has already issued a marketing authorisation in accordance with its national procedure.
Following this, further marketing authorisations can be sought from other EU countries whereby
the countries concerned (concerned member states, CMS) based on the RMS's assessment report
are requested to agree to recognise the validity of the original, national marketing authorisation
(including the Summary of Product Characteristics (SPC), package leaflet and labelling text),
unless they have objections on the grounds of a potentially serious risk to public health. In such
situations, further discussions will be held in the Coordination group for Mutual recognition and
Decentralised procedures (CMD(h)) (European Medicines Agency (EMA), 2014); (The Heads of
Medicines Agencies website (HMA), 2014).
The following section provides an overview of implementation of regulatory approval procedures
and shows their impact on the future of the MP status.
3. Impact of regulatory approval procedure on future regulatory status of medicinal
products
Strategic thinking by switching application is extreme important as it has impact on the
outcomes. This can be confirmed in this section through the following examples of case studies
with different strategies for granting approval for Rx-to-OTC-Switch.
3.1. Case study-Pantozol®
Even not innovative medicinal products can have access to centralised procedure, e.g. through
their eligibility for CP on the basis of their benefit for patients at Community level (see
subsection 2.4.2, mandatory and/or optional scope for CP). The case of Pantozol Control® switch
serves as an example within this context.
26
Background
The pharmaceutical company Nycomed achieved five MAs for medicinal products not subject to
medical prescription: PANTOZOL Control®, PANTOLOC Control®, PANTECTA Control®,
SOMAC Control® and CONTROLOC Control®, all containing 20 mg pantoprazole as active
pharmaceutical ingredient. Pantoprazole is the first proton pump inhibitor (PPI) that received
European wide OTC MA and is the second OTC product that received approval in the CP after
Glaxo Group Limited received the centralised OTC status in July 2009 from the European
Commission for alli 60 mg hard capsules (with orlistat as active ingredient) (EMA, 2009).
Pantoprazol is a PPI indicated for symptoms of stomach and intestinal gastric ulcers, heartburn,
Gastro-Oesophageal Reflux Disease (GORD) and other related gastrointestinal diseases. PPIs are
considered today as first line treatment for repeated heartburn and other reflux symptoms by
gastroenterologists, and are widely prescribed. Most people suffer from heartburn occasionally,
mainly after a meal. By definition, heartburn is the cardinal symptom of GORD, and not a
disorder by itself. The patients who suffer from reflux symptoms like heartburn often feel
uncomfortable that it affects the way they live their lives. Therefore the treatment of this
unpleasant condition has an important significance, above all as OTC medication (EMA,
European Public Assessment Report (EPAR), 2009); (Rathgeb, Anja, 2010).
Under a variety of brand names the prescription-only medicinal product is marketed in more than
90 countries according to information available on Nycomed’s homepage.
Through a Supplementary Protection Certificate (SPC) the validity of the basic patent for
pantoprazole could have been prolonged from June 2005 until May 2009 in most of the EU
countries. After patent expiry, Nycomed had to develop a successful strategy in order to avoid
share loss regarding pantoprazole as one of Nycomed’s key products caused by several generic
competitors expected to enter the EU market.
Strategic Options
• The first move Nycomed did was a short term defending of its pantoprazole turnover from
generic competitors by introducing an own generic product within several European countries
(for example in Germany by the launch of Pantoprazol NYC in December 2008).
• As a second move, Nycomed launched in 2009 an over-the-counter presentation of
pantoprazole in the EU for the treatment of heartburn.
27
OTC product application
The first medicinal product containing pantoprazole was not authorised via the CP. Therefore, the
OTC product application has no automatic access to the CP. So it was nesaccery to apply for
eligibility to the CP. In December 2007 the eligibility for an application of pantoprazole
containing OTC product to the CP was agreed upon by the EMA and CHMP. The eligibility was
granted under article 3(2)(b) of Regulation EC/726/2004 which describes one of the optional
possibilities to enter the CP. The eligibility was grounded on the demonstration of “interest of the
patients’ health at Community level” based on the rationale that the desire for an optimal self-
treatment of heartburn is universal and applies to patients throughout the Community.
Strategic implementation
On 28 April 2008 Nycomed applied for the initial MA for PANTOZOL® Control, containing 20
mg pantoprazole in gastro-resistant tablets. Furthermore, the change from prescription-only to
OTC medicinal product was proposed within this application by the applicant. Detailed
information regarding the assessment of this switch application is available at EPAR
EMEA/H/C/00101316.
Due to the fact that no centralised MA had yet been granted to Nycomed by the European
Commission (EC), the applicant had to apply for a complete new MA. The legal basis of this
OTC submission was based on article 10(3) of Directive 2001/83/EC, as amended, i.e. a hybrid
application:
In cases where the medicinal product does not fall within the definition of a generic medicinal
product as provided in paragraph 2(b) or where the bioequivalence cannot be demonstrated
through bioavailability studies or in case of changes in the active substance(s), therapeutic
indications, strength, pharmaceutical form or route of administration, vis-à-vis the reference
medicinal product, the results of the appropriate pre-clinical tests or clinical trials shall be
provided.
Pantozol 20/40 mg gastro-resistant tablets from the German market were selected as reference
product that differs from the applied OTC medicinal product in their authorized (Rx) therapeutic
indications.
In order to give consideration to the targeted legal status of a medicinal product not subject to
medical prescription Nycomed had to adjust the therapeutic indication. The following indication
was proposed in this initial application: “Treatment of reflux symptoms (e.g. heartburn, acid
28
regurgitation)”16. The recommended dose was 20 mg per day for total treatment duration of 4
weeks.
The CP officially started on 28 May 2008 for the initial application. The applicant then further
submitted four parallel applications of the same medicinal product with the only difference in the
product name: PANTOLOC Control®, PANTECTA Control®, SOMAC Control® and
CONTROLOC Control®.
As per application only one product name can be selected within the CP and due to the fact that
Nycomed has several brand names for its prescription-only product they had to submit parallel
applications. The Committee for Medicinal Products for Human Use (CHMP) opinion was
adopted for all five applications in parallel.
Results/ Discussion
On 20 to 23 April 2009, the CHMP issued a positive opinion with respect to the OTC status of
pantoprazole 20 mg gastro-resistant tablets within the context of a new, i.e., restricted,
therapeutic indication.
The European Commission adopted the positive CHMP opinion on 12 June 2009 and granted the
corresponding MAs (MA numbers EU/1/09/515-519/001-004). The approved indication is:
Short-term treatment of reflux symptoms (e.g. heartburn, acid regurgitation) in adults.
According to the above mentioned European Commissions’ recommendation different legal
statuses for the same medicinal product should not be available within one Member State.
Therefore in Germany the Expert Advisory Committee for Prescription-Only Issues was
authorised by the Federal Ministry to evaluate if pantoprazole in a single dose of 20 mg per unit
could generally be excluded from the AMVV.
Conclusion
Nycomed had approved MAs available within several EU Member States for the Rx product of
pantoprazole 20 mg tablets out of MRP/ DCP. Therefore the generic competitor had the chance to
enter several EU markets in parallel with a generic OTC product in a short time period.
In principle, Nycomed had triggered the following steps:
• Step 1: Submission of a generic application for the Rx- product via CP
• Step 2: Submission of a European type II variation in parallel in order to adjust the current
MA of the Rx product to the proposed OTC legal status which implicates the adaption of the
29
medical texts and the pack sizes-indication and dosage- as the eligibility to the CP would be
given due to the fact of being a generic product of a centralised approved product,
• Step 3: Submission in parallel of an OTC application for Rx-generic competitor product that
has been approved via CP and then adjusted through variation application.
So in general before the market entry of the generic OTC products could take place in a
respective Member State, the legal status of pantoprazole 20 mg had to be changed in the national
law. Considering the example of pantoprazole in Germany the AMVV was changed in January
2010 and therefore 27 non-prescription generic OTC products could be launched already six
months after the central OTC approval of Nycomed.
3.2. Case study-Vaprino®
Background
Racecadotril has first been authorized in France since 1992 for the treatment of acute diarrhea. It
is available on prescription as 100 mg hard capsules. The first OTC product was achieved in
Bulgaria in 2005. In Germany there were 6 Rx products containing Racecadotril of which two are
100 mg hard capsules (each CMS procedure, parallel import). So its application is limited to use
in adults.
In 2013, Boehringer Ingelheim launched 100 mg racecadotril tablets in Germany under the brand
name Vaprino® following a switch to non-prescription status for the active ingredient.
“In general the basis for the prescription of medicinal products is laid down in § 48 of the
German Medicinal Products Act (AMG). Within this paragraph the Federal Ministry is
empowered to specify substances which can be sold in Germany only on medical prescription.
The resulting legally binding text is the Ordinance on Prescription-Only Medicinal Products
(Arzneimittelverordnung für Verschreibungspflicht (AMVV)). Within the annex I of the AMVV
all active substances are listed which are available in Germany only on medical prescription.
Exemptions are possible meaning that special pack sizes can be excluded from the general
prescription-only status. [….] But the prescription-only status cannot be repealed until at least
three years have elapsed since entry into force of the ordinance on which it is based.” (Rathgeb,
Anja, 2010).
30
OTC product application
Boehringer Ingelheim GmbH & Co KG submitted according to § 48 AMG an application for a
nonprescription status of medicinal products containing racecadotril for usage in doses of up to
100 mg ("Meeting of the Expert Committee for Prescription"_Protokol 69, 2012).
Subject of the application was the request for waiver of prescription (§ 48 and § 53 AMG)
racecadotril 100 mg capsules.
The change in the legal classification was thought to be valid for the following conditions:
• Abolition of prescription for racecadotril 100 mg hard capsules
• Indication: Symptomatic treatment of acute diarrhea in adults (+ 18 years) as an easily
recognizable typical OTC indication
• Duration of use: max. 3 days
• No concealment of serious disease
• Dosing regimen: 1x 100 mg capsule initial + max. 3 capsules per day (1 + 3, 3, 3)
Package Size: max. 10 capsules.
However, Germany’s Expert Committee for Prescription, which is composed of 15 members
representing the pharmaceutical industry, healthcare professionals, pharmacies and other experts,
recommended that racecadotril should remain under prescription (BfArM- “Meeting of the
Expert Committee for Prescription“, 2012).
Further strategic approach
Under section 4.3 of the “Best Practice Guide for Authorisation of non- prescription medicines in
the decentralised and the mutual Procedure” (EMA, 2014), the Coordination Group for Mutual
Recognition and Decentralized procedures for human use (CMDh) explain the following option:
“This will result effectively in duplicate MAs in the chosen RMS and CMS(s) with separate
prescription and nonprescription product particulars (SmPC, label and leaflet). In doing so the
applicant must fully justify why a change in RMS is required. A product authorised in this way
may require a new name or distinct qualifier in line with national procedure.
In general, from a MRP European MA a national procedure can be initiated in order to grant a
MA as a duplicate of the original one. Therefore two MAs can be available for the same product.
In the case of racecadotril this means:
1. a MA of 100 mg hard capsules via MRP, (European authorization)
31
2. a MA of 100 mg capsules, hard capsules as a duplicate of the above mentioned MRP
authorized product which is granted via pure national procedure.
Under these circumstances, using the national regulatory framework and in accordance with §29
AMG and the EU Variation regulation 1234/2008/EG, it would be possible to change a marketing
authorization so that it will still comply with conditions for the prescription obligation but is
available OTC at the same time under specifically pre-defined conditions such as a restricted
indication etc..
Part one of the “Guideline on changing the classification for the supply of a medicinal product for
human use”, describes the “Criteria for classifying a medicinal product as subject to a medical
prescription or not and how to determine if a medicinal product does not meet these criteria and
may therefore not be subject to a medical prescription”. It specifies the four criteria mentioned
within the Article 71(1) of Directive 2001/83/EC and defines the basis of the correct
classification of medicinal products. In the end of this part it is highlighted, “that even if one of
the four criteria is applicable for a medicinal product it can be classified by a competent authority
as OTC product if specific conditions are fulfilled. The guideline herein also refers to Article
71(4) of Directive 2001/83/EC. In this context a specifically defined pack size which perfectly
fits to the length of treatment could justify a classification as OTC product even if any of the four
criteria is fulfilled. Besides of the pack size also the maximum daily dose, the maximum single
dose or the packaging type could turn the balance to OTC status.
In summary it means that a medicinal product for which any of the criteria on EU level applies
could have OTC status on a national level if specific precautions are appropriate for the national
competent authority.” (Rathgeb, Anja, 2010). This means that a variation application can be
submitted under specific conditions (e.g. OTC- indication, limited dosage, treatment period, etc.)
and a reclassification of the national MA might be possible.
Results of the used National/ DCP /MRP option
Once the requested reclassification had been granted on a national basis and Boehringer
Ingelheim had achieved a national OTC Market Authorization (in Germany), a MRP procedure
could be initiated in the concerned member states (CMS) within the EU for the appropriate OTC
product. This approach by using the duplicate MA under these circumstances corresponds to the
above mentioned option recommended by the CMDh (s. a.).
32
Conclusion
Boehringer Ingelheim had reached the reclassification of Vaprino in Germany. This might be
intended to be followed by submission of an MRP application in many CMS in the future, while
the prescription product is still on the EU market ("Meeting of the Expert Committee for
Prescription"_Protokol 69, 2012).
In principle the company had initiated the following steps:
• Submission of a national application for the product (duplicate)
• Submission of a European type II variation in order to adjust the current MA of the Rx
product to the proposed OTC legal status which implicates the adaption of the medical texts
and the pack sizes, etc.
• Change of the legal status at national level followed by separately submission of several
national variations in each concerned member state (CMS) in the context of an MRP
Procedure.
3.3. Case study-Viagra®
Background
Viagra has been authorised in the European Union (EU) since 14 September 1998 for the
treatment of men with erectile dysfunction. It is available on prescription as 25, 50 and 100 mg
film-coated tablets. Viagra 50 mg was expected to be used for the same indication but without a
prescription, as an OTC medicine.
Its manufacturer Pfizer believes that Viagra has the potential to be switched as it meets the
criteria set out by the European Commission guideline for changing the classification of a
medicinal product to non-prescription. Therefore, on November 8, 2007 Pfizer submitted a type II
variation application to switch Viagra (active ingredient: sildenafil) 50 mg film-coated tablets from
‘medicinal product subject to prescription’ to ‘medicinal product not subject to prescription’
through the European Medicines Agency's centralised procedure (EMA) . However, in an official
letter, Pfizer later notified the EMA its intention to withdraw its application regarding the change
of legal status of Viagra 50 mg. The withdrawal was justified by recognising concerns in terms of
the proposed supply of Viagra 50 mg tablets as non-prescription medicine across the EU. Pfizer’s
withdrawal aimed at enabling the evaluation of further information and the supply of additional
33
data that may be required to allow any future assessments under the centralized procedure (EMA,
2008). This information is based on a press release published on www.emea.europe.eu and the
European Public Assessment Report (EPAR) for Viagra available at the EMA website
http://www.emea.europa.eu/humandocs/Humans/EPAR/viagra/viagra.htm.
According to article 71 of Directive 2001/83/EC, as amended and the European Commission
Guideline on “Changing the Classification for the Supply of a Medicinal Product for Human
Use” (January 2006), the MAH considered that sildenafil 50 mg no longer meets the criteria for
classifying the product as subject to medical prescription, and therefore proposed to change its
classification to not subject to medical prescription”.
However, the Committee for Medicinal Products for Human Use (CHMP) did not follow this
consideration and did not recommend the applied change of the legal status:
Reasons for not recommending a change of the legal status
The main objections highlighted by the CHMP to exclude a recommendation for changing the
classification of Viagra 50 mg, relate to the following deficiencies:
1. Unsupervised use of OTC Viagra could delay the diagnosis of underlying diseases, such as
coronary artery disease, for which erectile dysfunction (ED) can be an indicator.
2. Viagra's proposed package insert was considered too complex and patients may require a
physician's input to avoid unintentional misuse.
3. Potential danger of increased misuse: OTC availability of the drug could lead to increased
recreational usage (especially in young patients).
Results
Based on the arguments mentioned above Pfizer couldn’t achieve a centrally granted OTC
Market Authorisation for Viagra (active ingredient: sildenafil) 50 mg film-coated tablets.
Discussion- Strategic recommendation
According to the author of the present work, applying a decentralised procedure (DCP) might be
another option to achieve OTC status for Viagra 50mg. However, the switch strategy would then
be limited by a market by market switch. By applying this type of procedure the following
34
obstacles and/or challenges associated with switching Viagra via DCP should be taken into
account:
• Certain country specific differences and requirements despite harmonization measures within
the EU
• Divergent views amongst Member states (MS’s) due to different national implementations of
European law or differing national law
- DCP+MRP procedures might include countries not willing to accept similar legal status
outcome in view of pack + package label + leaflet specifics
- Differences in reimbursement/health systems
- Differences in the opinion of various health care insurances within the MS’s
Conclusion
Using the DCP Procedure is not the most appropriate solution for Pfizer especially when the
intention was granting a MA for entire of the EU. This option still gives an opportunity to market
in some of the EU MS’s. As a market by market switch, this could result in the availability of
Viagra 50 mg as non-prescription in a few MS’s despite the differences within the EU.
However, under other conditions such as when an appropriate strategic pathway is selected in the
context of the regulatory environment Viagra could be successfully switched. This might be
indicated by successful patent extension of Viagra has been reached in the US via Switch. As
prediction, a switch attempt is to be expected in the EU since a “Withdrawal of an application
does not prejudice the possibility of a company making a new application at a later stage.” In this
regard, more information is available at EMA’s website:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2009/11.
35
4. Sources and methods for monitoring and analysis to achieve regulatory competitiveness
4.1. Monitoring and analysis of the legal framework and constantly changing regulatory
landscape
“The Regulatory Environment is always changing and always challenging. Increasingly,
Regulatory Affairs Department is seen as the department that makes things happen” (R.B. (Large
Multinational Pharmaceutical Company)), (Topra, 2012).
With much discussion revolving around the peak of the “patent cliff”, 4 of the top 10 once
biggest blockbuster products have experienced patent expiry during 2012 alone. With the
resultant loss of revenue (estimated to be approximately $140 billion annually) largely failing to
be off-set by new product pipelines and approvals over the coming few years, pharmaceutical
companies must evolve and innovate. Such innovation has led to a number of clear trends
developing over the past few years.
In the short term, line extension, reformulation, novel drug delivery mechanisms and addition of
new therapeutic indications for existing products have all proven to be successful strategies for
preserving revenue streams after patent expiration. In the longer term, the industry is
demonstrating a distinct trend towards the development of technologically innovative biological,
vaccine and orphan products and perhaps ultimately advanced therapies such as cell and gene
therapy. Other forms of revenue maximization come in the form of the penetration of Emerging
Markets, over the counter (OTC)-switching and an increased interest in generics by previously
innovator-only companies.
The movement towards innovation results in a steadily changing regulatory and health
technology environment. So governments are changing and evolving their regulatory
environments in response to global and local demands. This has consequences for pharmaceutical
companies. It leads the companies within the context of a well-known legal framework to be able
to compete with each other at an innovative level to secure and assure the best treatment for
patients.
In addition, in the face of counterfeit medicines and ever-tightening requirements for quality,
safety and efficacy, the regulatory environment has arguably ever been so challenging (Fisher,
2012). As a result, monitoring of the constantly changing regulatory environment plays an
36
essential role in the future success of the pharmaceutical industries. Driven by the increasingly
complex and challenging drug discovery process, pharmaceutical companies are regularly seen to
be also exploring innovative ways of generating revenue from already existing products.
4.1.1. Directives, regulations, guidelines: Impact on OTC status at an European and
national level
The early and comprehensive knowledge of in particular regulatory developments and
competitive activities plays a crucial role in the environment of the pharmaceutical industry in
terms of "Regulatory Intelligence" (RI) (see also subsection 1.2, Definition of RI) to secure
and/or expand a corresponding position in the market. In this context, one of the key activities of
the companies is to identify accessible data sources to develop a strategy or method in order to
ensure early delivery of business-related information.
"Regulatory intelligence" is based on "publicly available information sources". The next
paragraph gives an overview on those sources.
Legal and Health Authority related regulatory requirements – Current and Emerging
Before a regulation changes, the health authorities are usually signaling how their thoughts and
expectations are evolving. Knowledge of new legislation, regulations, and guidelines is of
importance in order to assess their future impact on company’s products, processes and strategies.
In addition, Health Authority related regulatory requirements may include recent government-
related events. These consist of, among others:
At EU level
Guidelines such as:
“Guideline on Legal Status for the Supply to the Patient of Centrally Approved Medicinal
Products”, (EMA/186279, 2006). The purpose of this guideline is to provide information
on changes to the Legal Status of an MP. It deals with the criteria to be followed by the
CHMP in determining the Legal Status of a medicinal product, as well as the
implementation of the Legal Status in the opinion of the CHMP. This guideline shall
apply to MP, authorized under the centralized procedure.
“Guideline on changing the classification for the supply of a medicinal product for human
use” (EMA/ Guidelines Revision 2006). This guideline is for use by marketing
authorisation holders applying to change the classification for supply of a medicinal
37
product. The guideline applies to all marketing authorisation granted in the Community. It
is also for use by competent authorities to facilitate harmonisation, within the
Community, of medicinal products restricted to medical prescription and of medicinal
products available without a medical prescription”.
This guideline consists of four parts:
- “Part 1 outlines the criteria for classifying a medicinal product as subject to medical
prescription or not.
- Part 2 outlines the data requirements for an application to change the classification
for the supply of a medicinal product from subject to a medical prescription to not
subject to a medical prescription.
- Part 3 outlines definition for the data exclusivity for data provided in a ‘switch’
application to describe the extent of data exclusivity in relation to significant pre-
clinical tests or clinical trials according to Article 74a of Directive 2001/83/EC
Part 4 outlines the principles and procedure to claim for one-year data exclusivity
based on Article 74a of Directive 2001/83/C”
(http://ec.europa.eu/health/files/eudralex/vol-2/c/switchguide_160106_en.pdf)
(European Commission Enterprise and Industry Directorate General, 2006).
At national level
The Ordinance on Prescription-Only Medicinal Products in Germany (Arzneimittel-
verschreibungsverordnung (AMVV)).
The amendments in regulations according to agreement on status change for the supply of a
medicinal product (Results protocol on prescription in accordance with the AMVV, (BGBl. I Nr.
75 from 28.12.2005, p. 3632), as amended, (BfArM, 2006).
The new regulation on the prescription of drugs is based on § 48 of the German Medicines Act
(AMG), which was fundamentally changed with the 14th amendment of the Medicines Act.
In this Regulation all prescription substances are listed. This also includes, in accordance with the
previous § 49 AMG (automatic prescription), prescription substances. However, the new
prescription drug regulation serves both, the regulatory authorities by facilitating their control and
surveillance activities and the legal subjects by making Information available.
38
Other requirements and/or references
• ICH-Guidelines
The International Conference on Harmonization of Technical Requirements for Registration of
Pharmaceuticals for Human Use in ICH-Region (USA, Japan, EU) brings together the regulatory
authorities and pharmaceutical industry of Europe, Japan and the US to discuss scientific and
technical aspects of drug registration. ICH's mission is to achieve greater harmonization to ensure
that safe, effective, and high quality medicines are developed and registered in the most resource-
efficient manner (Pharmaceutical industry trade groups, 2014). More details are available at
http://www.ich.org/. The purpose is to make recommendations for greater harmonization in the
interpretation and application of technical guidelines and requirements for product registration, in
order to reduce or eliminate the need to duplicate the test reach out during research and
development of new drugs. “The ICH does not develop legally binding guidance documents, but
its activities reflect the current state of the art and the “burning issues”. Many of the ICH
guidelines are transferred to local regulations with a certain delay” (Heyen, 2004) .
• World Health Organization(WHO)
Since ICH was initiated, in 1990, there have been observers to act as a link with non-ICH
countries and regions. One of the observers to ICH is the World Health Organisation (WHO).
In carrying out its missions, WHO’s secretariat focuses a. o. on the following core functions:
Negotiating and sustaining national and global partnerships
Setting, validating, monitoring and pursuing the proper implementation of norms and
standards
Stimulating the development and testing of new technologies, tools and guidelines for
disease control, risk reduction, health care management, and service delivery
More information in this regard, WHO- Guidelines and CT-Registries (Completed or In Progress)
are available at WHO-Website: http://www.who.int/medicines/information/websites/. Table 2
provides an overview on some of the Regulatory associations.
• Global Regulatory Agency’s web sites (e.g. EMA, FDA, HMA)
Agency’s website present guidance documents which are published for all areas of drug
development and support the interaction between industry and the agency. They represent the
agency’s current thinking on particular subjects and are not legally binding for the agency and the
39
sponsor, but it is advisable to have a good reason in place for not following them. Additionally,
other beneficial information is provided such as
Advisory committee updates
EU-Approval information- EPARs or FDA approval letters (see also subsection
4.4.2.1.1(B).
Regulatory agency’s interactions, meetings
Warning letters
Regulatory decisions
Withdrawals from Market and reasons
Post marketing Commitments and Status
- Post marketing requirements and commitments/Safety requirements
- Post marketing Assessment Safety/Efficacy studies (PASS/PAES)
For more details on HMA see also subsection 4.4.2.1.1(A).
European medicines regulatory authorities are linked to each other through Regulatory Networks
e.g. “European Union Drug Regulating Authorities Network (EudraNet)” (table 3). More details
are available on EMA website http://www.ema.europa.eu/ema.
• Clinical Trial Registries (CT-Register)
CT-Registries provide data on clinical trial such as
Number /type of studies and endpoints, target populations (age/gender), comparators, and
safety issues (e.g. clinical hold)
CT-Registries e.g. WHO, IFPMA, EUDRACT, NIH/NLM (Table 4 and subsection
4.4.2.1.1(E))
• Marketing Authorisation-database (MA-Database)
MA-database provides information available on similar approved products e. g. EU-Approval
Rapporteur and Co- Rapporteur and Reference Member State (RMS). This data includes among
others the following issues
Therapeutic areas- OTC-category
Classification - Reviewed by same division
Regulatory pathway/regulatory strategy used
40
Decision – not approvable, approvable, or complete response
Number of review cycles, timing, and reason(s) for multiple cycles
For EU approval - Rapporteur and Co-Rapporteur and reference member state
• Additional Regulatory environment-Sources:
Industries and trade associations:
Trade Associations such as European Federation of Pharmaceutical Industries and
Associations (EFBIA) and the Pharmaceutical Research and Manufacturers of America
(PhRMA) intend to make CT more transparent (IFPMA Clinical Trials Portal) (see also
subsection 4.4.2.1.1(F)
“Regulatory Intelligence” (RI)/Research providers and RI sites
Regulatory Affairs Professionals Society (RAPS) ( www.raps.org/)
Regulatory Organisations e.g. “The Organisation for Professionals in Regulatory Affairs”
(TOPRA) (Topra, 2012); (Felgate, Tim; Applied Regulatory Consulting, 2011).
The Federation of Associations of Regulatory Boards (FARB)
41
Table 2: Overview on Regulatory Associations - EU/US
Regulatory Associations-EU Regulatory Associations-US
• The European Society of Regulatory Affairs
(ESRA)
http://ww2.esra.org/Resource.phx/communit
y/mainpage/mainpage.htx
• The UK's British Institute of Regulatory
Affairs (BIRA) ( ESRA equivalents)
• The Association Française des Affaires
Réglementaires, (ESRA equivalents)
• The Società Italiana Attività Regolatorie
(ESRA equivalents)
• Deutsche Gesellschaft für Regulatory Affairs
e.V (DGRA) –
German Society for Regulatory Affairs:
Regulatory information on Guidance &
Guidelines
• WHO-Website: Complete List of Regulatory
Agencies in the EU and around the world
(http://www.who.int/medicines/information/
websites/infdra.shtml)
• The Regulatory Affairs Professionals
Society (RAPS): provides its members
with information o. a. on medical devices
and pharmaceuticals. This international
organization holds workshops and annual
meetings on regulatory affairs.
• The Center for Regulatory Effectiveness:
ensures that the information used to
develop federal regulations is accessible
to the public. The site also maintains a
listing of regulatory think tanks, which
provide a variety of services such as data
analysis and regulatory litigation reports.
• The American National Standards
Institute:
- It seeks to promote and facilitate
voluntary standardization practices in
the U.S. This private, nonprofit
organization plays a vital role in
regulatory affairs.
Source: (Regulatory Intelligence Working Group, Regulatory Intelligence, 2010); (Topra, 2012).
42
Table 3: Overview on Regulatory Networks- EU/US
Regulatory Networks-EU Regulatory Networks-US
• European Union Drug Regulating Authorities
Network (EudraNet):
A network in the field of European human and
veterinary pharmaceuticals whose remit is partly
to enable communication and the sharing of
information and databases between the European
Commission, EMEA, and the national Competent
Authorities in pharmaceuticals.
EUDRANET supports include:
o Pre-submission support
o Post approval support (pharmacovigilance of
products on the market, adhering to European
national and regional regulations)
o The dissemination of relevant information to
industry, scientific experts and regulators.
• The Regulatory Affairs Information
Web site http://www.rainfo.com/
It offers a diverse mix of Internet sites such
as the latest worldwide RA news, listservs,
Food and Drug Administration (FDA)
forms, and online RA journals.
Source: (Regulatory Intelligence Working Group, Regulatory Intelligence, 2010) and (Topra,
2012).
4.1.2. Market analysis: Regulatory climate and developments regarding OTC status within
various EU member states
The analysis and interpretation of gathered information on the market is necessary in order to
serve strategy decisive measurements and/or activities such as forecasting of regulatory activities
of specific competitors, e.g. its life cycle management and/or future strategies such as Rx-to-OTC
switch, status change of medicinal product into medical device or cosmetics.
There are different legal and regulatory requirements despite harmonisation. In the context of
switch activities, differences in the national implementing of the EU- Guidelines regarding
classification of medicinal products can be beneficial but also challenging in the development of
switch strategies. It can be beneficial when e.g. under certain circumstances and in the context of
43
specific regulatory requirements a switch strategy might be successful and the appropriate
medicinal product achieves its new desired OTC status as expected.
4.2. Monitoring and analysis of Competitor activities
For determination of the competitive and market situation, there are specific tools and techniques
that can be used for the daily competitive analysis such as competitor profiling, timeline analysis,
competitive portfolios, financial analysis, SWOT analysis, etc. This requires ongoing
collaboration between regulatory, scientific, medical and marketing (commercial) functions, as
different departments use different tools and focus on different aspects. This process should then
automatically be followed by final data filtering based on departments’ specific issues and used
sources and techniques. When regulatory sources mentioned in subsection 4.1.1 were used and
relevant regulatory information gathered, analysis of evolving competitors' strategies is
substantially for the grading of possible concerns.
In the context of the methodology (see also subsection 1.4) applied in this thesis and in
accordance with the results generated from the interviews performed with employees of different
disciplines confirmed that the collaboration between various departments within the company
plays a crucial role in the planning of a strategy.
Figure 4: Overview of a few “Regulatory Intelligence” involved disciplines.
The following provides an overview about the departments involved (Figure 4) and the sources
and tools they use in the analysis of competitor activity:
44
Market Research-
Market research comprises important functions with respect to the monitoring and analysis of
competitors: i.e.:
• analyzing the sales, marketing and medical affairs activities of leading pharmaceutical and
biotech firms around the globe.
• obtaining insights into competitor categories, best practices, target markets, sales force
deployment, pharmaceutical product strategies, and more.
• competitive monitoring:
competitive benchmarking of organizational structures and practices
pharmaceutical business intelligence about marketing spendings by individual brand and
indication
Regulatory Affairs- Using MA-DB & Agencies’ web sites
The regulatory affairs department may contribute to competitor tracking by monitoring of
regulatory aspects regarding main competitors, such as:
• Same area of indication/ mode of application, phamacovigilance aspects, recent launches in
the target regions/countries, recent MA withdrawals/ rejections, subject of advisory board
meetings, subjects to interesting special subgroups (Heyen, 2004),
• Marketing authorisation database e.g. EudraPharm provides input about product/ competitors’
authorisation procedure(s) (National, CP, MRP/ DCP). This type of data can be found in MA-
Database, at the web site of Heads of Medicines Agencies (HMA), “European Product Index”
(see also sub section 4.4.2.1.1(C)) and
• Monitoring of Agencies’ web sites for all relevant published regulatory agency materials.
Marketing-
Within the context of marketing activities, contribution activities are more oriented towards
market share of drugs already available on the market, expected market share of drugs under
development, market size, and financial power of the market. Moreover, the tracking and
reviewing competitors’ promotional material belong to the core functions of the marketing
department when it comes to competitor monitoring and analysis.
45
Scientific Affairs- Using CT-Database
There is a relevant impact of scientific data evaluation provided by the Scientific Affairs
department with respect to competitors’ future strategy in the context of drug development and/or
launch strategy.
It provides insights on medical needs in the community e.g. for the target indication in the target
region/country. The evaluation of gathered data from e. g. the CT-database such as EudraCT by
the Scientific Affairs-department could be of importance as based on the design of the clinical
trials one might assume e.g. the intention of the competitor company in terms of e.g. therapeutic
indication, target populations dosage, pharmaceutical form, etc. (Table 4 “Clinical Trial-
Registry”).
Respective clinical trial databases contain data on
• the sponsor, the design, the drugs to be tested, the results reports,
• the application areas and objectives of the clinical trial and
• clinical trial inclusion and exclusion criteria
In addition, there are many other additional regulatory sources that can be used in order to serve
regulatory intelligence activities such as patent searching, trade journals and annual reports and
other company’s literature, etc.
Analysis and Filtering of gathered data
After data of different sources have been gathered and analysis procedure has been finished,
filtration process can be initiated by classification of the importance and significance of the
collected information. Subsequently, information is communicated to the respective departments
for appropriate evaluation (Figure 5 and 6).
46
Figure 5: Overview of “Regulatory Intelligence” involved disciplines.
4.3. Discussion and Conclusion
4.3.1. Discussion
Various involved departments provide an analysis and interpretation of gathered information
based on different applied tools in the context of interpretation and analysis as well as various
regulatory sources in order to serve strategy decisive measurements of events and/or activities.
The following example demonstrates these events.
For Example: The Scientific Affairs department receives from the marketing department a
notification that a new competitor product has been introduced to the market. This statement must
be verified by different departments. For example, the “Scientific Affairs” should verify if
eventually there are any clinical trials of a competitor product are registered. In this case CT-
Registries would be the appropriate data source.
Another case would be, if the notification was regarding a reference to a new / revised regulatory
approval or marketing authorization application, or when it is about new combination of active
substances and/or in a new Over-the-Counter recommended dosage. Here, the “Regulatory
47
Affairs” will be responsible for the verification of this statement. In this case Marketing
Authorisation-Database would be the appropriate data source.
However, consequently, these statements must be verified. In order to do so, various departments
of the company need to collaborate and exchange their analysis - based on the department
specific tools- of the information circulated.
Activities need to be communicated include e. g.:
• forecasting of regulatory activities of specific competitors for e.g. its life cycle management
and/or future strategies such as Rx-to-OTC switch, and medicinal product to medical device
or to Cosmetics
• grading of possible concerns
Each department should communicate and/or notify the respective gathered data to Regulatory
Affairs department in order to
• better and early prepare for a strategy in the market(s) analysed,
• prepare a strategic planning (e. g. for new switch strategy)
Figure 6: Overview of “Regulatory Intelligence” involved disciplines and their interactions.
48
4.3.2. Conclusion
In this thesis based on the results generated from the applied methodology show that the
communication and/or dissemination of gathered data between the departments plays a crucial
role in the development of a company future strategy! As the notification of each department to
Regulatory Affairs department aims at to better and early prepare for a strategy in the market(s)
analysed e.g. preparing for a new switch strategy. However, consequently the communication
between all involved disciplines has become a necessary part of business models for research-
driven pharmaceutical companies.
To make all this happen, regulatory data transparency is the core of these events.
In case there is a need for information can’t be found on any agency’s website, alternatively it is
possible to submit a request to the respective agency. When information is not available for
example on FDA's Web site, submission and processing of a Freedom of Information (FOI)
Request is possible in order to obtain information required and of interest.
The following subsections describe how among others authorities and institutions contribute to
make regulatory data transparent as possible.
4.4. Data Transparency
4.4.1. Freedom of Information Act
When information is not available on e. g. Agency’s web site, submission and processing of a
Freedom of Information (FOI) Request is possible in order to obtain information required and of
interest.
1996 amendments to the Freedom of Information Act (FOIA) mandate publicly accessible
"electronic reading rooms" with agency FOIA response materials and other information to be
routinely available to the public, with electronic search and indexing features. Available at FDA
home page: http://www.fda.gov/RegulatoryInformation/FOI/default.htm.
In order to satisfy the constant commercial desire to stay ahead of the competition by maximizing
product differentiation ongoing collaboration between regulatory, scientific, medical and
49
commercial functions is required. Figure 3 presents an overview of disciplines involved in
“Regulatory Intelligence”.
4.4.2. European Transparency Policy
Transparency represents a key element within the European Union (EU). It has been entered as
one of the declarations, declaration 17 of the so-called “Maastricht Treaty” entitled “on the right
of access to information”. It states that “transparency of the decision-making process strengthens
the democratic nature of the institutions and the public's confidence in the administration” (The
Treaty on European Union, 1992).
There might be tow kind of categories, proactive and reactive transparency.
While proactive transparency describes the automatic provision of information by regulatory
authorities e.g. by publication on internet websites, accessible databases or as printed documents
and may cover administrative as well as scientific information, reactive transparency describes
the access to documents on demand.
The reactive transparency approach refers to information held by the regulatory authorities,
including documents prepared by authority members and third-party documents.
On the EU level Regulation (EC) 1049/2001 rules the public access to information held by the
European Council, Parliament and Commission. The aim of this provision was to establish rules
and procedures to ensure "on grounds of public or private interest ... the widest possible access to
documents' of the three institutions” (Article 1) (Regulation (EC) No 1049/2001, 2001).
At present, there is no harmonized legislation on the disclosure of official information held by
national authorities. Therefore, the access to documents is ruled by individual national provisions.
However, governments are making efforts in order to make the transparency more effective and
to serve the public interest better.
The following subsection(s) provide an overview on the role of publicly available regulatory data
within the context of competitive intelligence.
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4.4.2.1. Possible sources for Regulatory and competitive intelligence data
In short, regulatory intelligence- specialists must keep up with the latest advances and
development in the regulatory environment. In principle, all publicly available information
mentioned in sub section 4.1.1 can be applied in order to gather information on competitor(s).
Ideally, this information covers the entire competitor’s life cycle. Data can be gathered during the
competitors’ development phase from e.g. clinical trials (CT)-database such as EudraCT
(4.4.2.1(E)) and after MP approvals from various MA-Databases where information on e.g. line
extensions, renewals, and new therapeutic indications are available. Sources as regulatory
intelligence databases, up-to-date information on regulatory websites, EU Guidelines and
Directives, as well as their amendments and new drafts including their national implementation
within the EU are necessary in developing a regulatory strategy.
In addition, data to track and monitor post-approval safety/efficacy studies (PASS) and (PAES)
are available in the European pharmacovigilance database, EudraVigilance database
(EMEA/187439/2006/Final, 2008).
As mentioned above, in general, in order to monitor competitors, monitoring and tracking of
regulatory Guidelines and requirements as well as regulatory environment plays a decisive role in
strategy development in a competitive world. Therefore, to keep up-to-date it is important to
• subscribe to newsletters/journals for tracking of EU regulatory updates such as Regulatory
Intelligence, EU Guidelines, Regulatory Networks (EudraNet), EU Pharmaceutical News
• participate in conferences as some of the most useful regulatory intelligence cannot be written
down, yet might be gathered by oral conversations/talks within the context of relevant
conventions. So participating in conferences might be helpful in gathering and updating
regulatory issues (e.g. attending a TOPRA conference and courses (www.topra.org/events))
(Regulatory Rapportuer, 2013); (Regulatory Rapporteur, 2011).
• share exchange of information (Industry/Trade working Groups)
"There are infinite ideas but finite resources"- RAPS- Developing regulatory strategy (Bill
Greenrose, 2008).
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4.4.2.1.1. Transparency Sources on European level
A. EMA: The New “Eudra Vigilance Medicinal Product Database Extended (EVMPD)”
expected by the end of 2014
The EVMPD- database (DB) is currently pending. As expected it should be completed by the end
of 2014 and be accessible as of the beginning of 2015.
There will be a public part for anyone interested which means that besides the pharmaceutical
companies the public has access to the data as well. This new database also intends to make
product information (SmPC and GI) available, which previously did not exist in this way.
Additionally, entries relating to safety data in this database will be serving the transparency
purposes. All occurring risk notifications are entered there. Previously, pharmaceutical
companies have not had an opportunity to update the data registered by them. The update process
should be allowed in the new platform. The information to be reviewed and updated comprises
details on:
• Legal basis (legal basis of the approval)
• Type of approval
• Approved dosage form (difference to the "administered" form).
Additional (new) requirements on data in the XEVMPD are:
• The future database provides an input option on outgoing MAH-Transfers (Change of
Ownership)/ renewals in the XEVMPD.
• When there is a change notification, SmPCs must be placed in the national language. This
concerns the procedures MRP and DCP.
• Implied timelines require
Notification of new registrations within 15 days
Notification of changes (change advertisements / variations except for Type IA) within 30
days after entry into force.
Of note, authorization holders’ own maintenance phase begins once the general revision is
completed - i.e. already within the transition phase before t December 31st, 2014. The timelines
for notifications are binding from that date.
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B. European Public Assessment Report (EPAR)
Detailed information regarding the authorised medicinal product is published as a European
Public Assessment Report (EPAR) on the homepage of the European Medicines Agency (EMA)
after granting of a MA by the European Commission. EPARs are full scientific assessment
reports of medicines authorised at a European Union level.
The EPAR reflects the scientific recommendation of the CHMP at the end of the CP after
deletion of commercially confidential information. EPAR provides comprehensive information
on the clinical and pre-clinical modules of the application for marketing authorization and rather
marginal information on the pharmaceutical quality as this is considered as commercially
confidential (EMA, Principles to be Applied for the Deletion of Commercially Confidential
Information for the Disclosure of EMEA Documents, 2007). Furthermore, the currently approved
product information texts (Annex I-III b of the EC decision, displaying the SmPC, the marketing
authorisation holder responsible for batch release, conditions of a conditional approval as
appropriate, labelling and PL) are available.
C. Heads of Medicines Agencies (HMA)
European Product Index
The Heads of Medicines Agencies (HMA), which represent the leaders of the competent
regulatory authorities of the EU member states, intend to smooth the way for a common approach
of the authorities regarding transparency as they are aware of discrepancies in the implementation
of the provisions of Directive 2001/83/EC and different national legal provisions concerning the
access to documents and the disclosure of information (EMA, 2008).
Under the following link “http://mri.medagencies.org/Human/product-information” a list with
National Competent Authority (NCA) websites can be found with links to their information on
Authorised Human Medicines, if available (as of October 2012).
German Databases to be accessed via the competent authority Paul-Ehrlich-Institut (PEI) contain:
Medicinal Product Information System (Arzneimittelinformationsystem, AMIS) on
PharmNet.Bund (see also subsection 4.4.2.1.2. below).
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D. The EMA and the European Network of Centers for Pharmacoepidemiology and
Pharmacovigilance (ENCePP)
The European Medicines Agency (EMA) and the European Network of Centers for Pharmaco-
epidemiology and Pharmacovigilance (ENCePP) have launched an electronic study register (E-
register). The E-register is publicly available and contains pharmacoepidemiological and
pharmacovigilance studies carried out by academic centers and other research organizations.
On the one hand, thereby it is intended to provide information on use, safety and efficacy of
medicines to be more accessible in the practice. On other hand, the effect of publication bias
should be reduced by the fact that positive and negative study results are recorded. The
registration of studies in the register is voluntary, unless the study is to contribute to the quality
guidelines "ENCePP study". The E-register is available on the ENCePP site:
http://www.encepp.eu/encepp/studiesDatabase.jsp (EMA, Press Release, 2010).
E. Clinical Trials
ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical
human studies conducted around the world. It is a service of the U.S. National Institutes of Health
(see table 5, Clinical Trial-Registry, www.clinicaltrial.gov).
European Clinical Trials- Database (EudraCT):
The European Medicines Agency has launched a new version of the European Clinical Trials
Database (EudraCT). This new version, EudraCT V10, marks the final step of a process through
which summary clinical trial results will be made publicly available through the EU Clinical
Trials Register (EU CTR), available at https://eudract.ema.europa.eu/ (EMA, 2008). EudraCT
V10 provides a list of fields for the result-related data contained in the EudraCT clinical trial
database to be made public in accordance with Article 57(2) of Regulation (EC) No 726/2004 and
its implementing guideline 2008/C168/02,
http://ec.europa.eu/enterprise/pharmaceuticals/eudralex /vol-10/2009_02_04_guideline.pdf.
54
Description
Data- Source
(e.g.)/Website
Germany The database contains information on clinical trials on
medicinal products approved in Germany. DIMDI
Europe
In the "EU Clinical Trials Register" (EU CTR) of the
European Medicines Agency (EMA), information can be
found on clinical trials that have been approved in other
European countries. The information from PharmNet.Bund -
Clinical trials appear there as well.
https://www.cl
inicaltrialsregis
ter.eu/
USA
ClinicalTrials.gov is a service of the U.S. National Institutes
of Health. It constitutes a registry and results database of
publicly and privately supported human clinical studies
conducted around the world.
http://www.cli
nicaltrials.gov/
Inter-national
(Clinical
trials outside
Europe)
The "International Clinical Trials Registration Platform" of
the WHO (WHO ICTRP) provides information on clinical
trials that have been approved in countries outside Europe.
Different registers provide their data to it, including "EU
Clinical Trials Register". WHO ICTRP thus contains global
data, including data from Germany and Europe.
International
Clinical Trials
Registration
Platform
Table 4: Overview of Clinical Trial-Registry
F. Transparency- Trade Associations
Besides trade associations such as European Federation of Pharmaceutical Industries and
Associations (EFPIA) and the Pharmaceutical Research and Manufacturers of America (PhRMA)
intend to make CT more transparent (IFPMA Clinical Trials Portal).
On July 24, EFPIA and PhRMA officially launched their joint Principles for Responsible Clinical
Trial Data Sharing to benefit patients (responsible data sharing). This commitment to data sharing
will improve research and scientific evidence, support patient care and improve public health.
55
According to the principles, (bio) pharmaceutical companies will dramatically increase the
amount of information to be made available to researchers, patients and the public.
(Bio) pharmaceutical companies are committed to enhancing public health through responsible
sharing of clinical trial data in a manner that is consistent with the following Principles:
• Safeguarding the privacy of patients
• Respecting the integrity of national regulatory systems
• Maintaining incentives for investment in biomedical research.
However data sharing is as common baseline on a voluntary basis. Therefore, in order to
encourage researcher, government to promote medical and scientific advancement the following
commitments need to be adopted and implemented:
• Improving data sharing with researchers
• Enhancing public access to clinical study information
• Sharing results with patients who participate in clinical trials
• Certifying procedures for sharing clinical trial information
• Reaffirming commitments to publish clinical trial results
The Implementation date of these commitments was January 1, 2014 (PhRMA and EFPIA,
2013). More details are available at
http://transparency.efpia.eu/uploads/Modules/Documents/data-sharing-prin-final.pdf.
4.4.2.1.2. Transparency Sources on a National level –Germany
A. AMIS- Database’ future name “AMANDA” with more transparency- Product Index
The German database accessible via the competent authorities BfArM / Paul-Ehrlich-Institut
(PEI) is “Medicinal Product Information System” (Arzneimittelinformationsystem, AMIS) on
PharmNet.Bund (see also subsection 4.4.2.1.1(C) above).
“The PharmNet.Bund-Drug Information System contains administrative data concerning the
authorisation of medicinal products as well as Summary of Product Characteristics (SPCs) and
Patient Information Leaflets (PILs). Further information on the drug information system can be
found in the database description of the German Institute of Medical Documentation and
Information (DIMDI).”
56
AMIS provides information on approved and formerly approved medicinal products; developed
by the German Drug Regulatory Authorities. AMIS future name will be “AMANDA” and it is
expected to provide more data transparency.
B. Clinical Trials
Clinical trial Information such as number /type of studies and endpoints, target populations
(age/gender), comparators and more can be found at clinical trial registries at
www.clinicaltrial.de. An overview of national (German) and international databases is provided
in table 4.
4.5. Consequences of potential Transparency
In brief, increased transparency in the end results among others in enhancing of e.g. competitor
data availability on issues such as
• Clinical trials (CT):
CT-design, CT-sponsor, drugs to be tested, (new) indication, route of administration,
population, etc.
(Clinical Trials source: e. g. EudraCT-database)
• Marketing Authorisation (MA):
MA-Granting,-Withdrawal, - Renewals, Patent expiry, etc.
(Regulatory source: e. g. AMIS-database)
• Post-Approval (PA) activities:
Post Approval- Studies:
- Post Approval- Safety Studies (PASS)
- Post Approval- Efficacy Studies (PAES)
(Regulatory source: e. g. Clinical Trials-Registries)
Post approval activities (Life Cycle Management):
- Agencies‘ variation notifications on Agencies‘ websites, (e.g. The Federal Gazette by
the BfArM (Bundesanzeiger))
- Renewals of the same MA
- New marketing authorisation with new type of indication, route of administration,
pharmaceutical form etc.
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- Switch issues include
- Prescription-to- nonprescription (Rx-to-OTC) switch
- Switching of Medicinal Product (MP)-to Medical Device
- Switching of MP- to –Cosmetics
Transparency has an impact on issues such as competitor analysis. E.g.:
• Identifying of switch candidates: e. g.:
Follow-on- drugs in switch categories
• Reviewing of indications for drug classes that have already switched
• Deep Assessment of safety profiles
Identifying of potential switch hurdles
• Reviewing and/or assessing of patent expiration timing
• Definition of likely approval requirements, investment and timeline.
However, transparency covers the entire life cycle of MP (pre-, during and post- approval
activities). Pharmaceutical industry’s initiatives and Governments encourage transparency for
better research and development to serve the public health better.
58
5. Overall Summary
The process by which a prescription medication moves from prescription to over-the-counter
(OTC) status for either the same or a related use is called Rx-to-OTC switch.
The reclassification of a drug and / or the associated indication (s) of Rx OTC status presents, in
general, a scientific data-driven and highly regulated process.
OTC medicines are strictly regulated and a number of regulatory processes have meanwhile been
developed to allow for new and approved products to be reviewed and approved in a clear and
transparent manner. For a medicinal product to be issued OTC status, it must possess both a
proven adequate safety margin and corresponding effectiveness. Consumer friendly and
understandable labeling to ensure self-diagnostic in the absence of medical guidance must be
secured.
The pharmaceutical industry is facing many challenges such as rising drug development costs,
increased competition and shorter periods of market exclusivity to maximize their return on
investment (ROI). Therefore, life cycle management strategies must be re-examined and
established through the pharmaceutical industry in order to proactively overcome these
challenges and optimize revenue stream. Product life cycle management (PLM) can encompass
many ways including reformulations, advanced delivery formulations, expanded indications,
fixed dose combinations as well as the assessment of opportunities to switch Rx drugs to OTC or
develop pre-authorized or branded generics.
However, one of the alternatives to extend brand life cycle of a Medicinal Product (MP) is to
develop a switch strategy of the MP from Rx-to-OTC. The timing of Rx-to-OTC switching will
depend on many external factors: These include patent expiration and generic erosion of the
parent compound, new Rx technologies to optimize delivery and line-extensions as well as the
OTC competitive environment and product labeling.
Depending on the regulatory switch strategy chosen the process can result in a successful switch,
it might take several months or years. But it might also completely fail. To be considered,
different types of Procedures result in the development of various strategies!
However, developing a switch strategy should be based on regulatory data to support the switch
process. Regulatory Intelligence (RI) data sources play a crucial role throughout the whole life
cycle of a medicinal product with regard to procedural, technical, scientific and strategic input.
This key role includes general data gathering and tracking legislation, followed by information
59
dissemination and utilization. Therefore, the use of all possible available sources for Monitoring
of Regulatory environment such as Guidelines and Directives and the legal requirements as well
as all other publicly available regulatory data at both national and international level is of
importance in order to achieve a successful European and global business.
In the context of Regulatory Intelligence in the development of OTC product strategy the sources
mentioned previously in section 4 should be well monitored, implemented and applied. Since the
Regulatory framework covers all phases of the product life cycle and considered to be the key
success driver, RI sources remain as the most important business success factor. (e. g. Switch
Guidelines: Classification Guidelines; “Guideline on Legal Status for the Supply to the Patient of
Centrally Approved Medicinal Products” etc.).
In order to develop a switch strategy there are some issues that need to be verified in advance.
These include among others selecting the type of procedure (CP/MRP/DCP NP), Competitor
Analysis and applying the assessment framework. Different types of Procedures result in the
development of different strategies.
Data transparency plays a key role in facilitating the tracking and monitoring of regulatory data
besides competitive/competitor strategies to complete the planning of a regulatory strategy.
Publicly available information sources became more valuable through strong transparence of
available databases such as the EMA- new database “Eudra Vigilance Medicinal Product
Database Extended (EVMPD)” on EU-level as well as on national level e.g. the German new
AMANDA-database.
The target subject of this master thesis is to present a general overview about possible approaches
based on possible regulatory intelligence sources, for developing a successful switch strategy of
the legal basis of medicinal product that has been recognized as a potential switch candidate in
respect to similarities, despite differences and challenges within the European Union. Through
the three mentioned study cases it has been confirmed that selecting of the right regulatory
pathway is an important strategic factor in order to achieve the success. Good knowledge in
regulatory framework including Directives, Guidelines, and amendments, as well as competitor’s
strategies, are considered to be essential as they play a decisive role in taking decisions regarding
business strategy.
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6. Conclusions and Recommendations
One of the alternatives to extend brand life cycle of a Medicinal Product (MP) available on
prescription is to develop a switch strategy of the MP from Rx-to-OTC. The timing of Rx-to-
OTC switching will depend on many external factors including, among others, patent expiration
and generic erosion of the parent compound, as well as the OTC competitive environment.
Depending on the regulatory switch strategy chosen, the process can result in a successful switch;
it might take several months or years. But it might also completely fail.
In general, different types of Procedures result in the development of various strategies. But since
the selection of an appropriate (switch-) Strategy determines which procedure is required, it is
recommended to decide on a specific strategy first and afterwards to select the best appropriate
procedure type!
In general, the Development of a switch strategy should be based on respective regulatory data.
Regulatory Intelligence (RI) plays a key role within the context. It includes general data gathering
and tracking legislation, followed by information dissemination and utilization. For this purpose,
identification and utilization of the appropriate relevant information sources for gathering of
respective data as well as constant monitoring is crucial. Reliable updates of the latter are of
importance. Therefore, the use of all possible available sources for monitoring of regulatory
environment at both national and international level is of importance. In the context of
Regulatory Intelligence and the development of OTC product strategy the sources mentioned
previously in section 4 should be regularly monitored as well as thoroughly checked. Excellent
knowledge in RI sources remains as the most important business success factor. In order to
develop a switch strategy there are some issues that need to be verified in advance. These
include, among others:
Selecting the type of procedure (CP/MRP/DCP NP), and reviewing of the eligibility to apply
the centralised procedure (CP) in the context of CP “mandatory” or “optional” scope.
However, despite harmonization, it must be considered that significant differences among the
EU member states in the national implementation of the EU Regulation still exist.
Competitor analysis is required e.g. for identifying Switch Candidates
Different types of Procedures result in the development of different strategies. There is a diverse
collection of national OTC markets in the EU with little harmonisation across the countries. The
EU is attempting to harmonise the self-medication markets in the region via Europe-wide
61
switches, but there are still significant differences. The European centralised switch procedure
allows the pharmaceutical industries to obtain one single MA for the 28 EU member states (e.g.
Pantoprazol 20 mg, approved in 2009(see also case study –Pantozol®)). The mutual recognition
procedure means that a MA granted via national procedure can be applied to obtain MA in
another member state (e.g. 100 mg racecadotril, approved in 2013(see also case study –
Vaprino®)). This can be denied regarding “potential serious risk to public health” where the
matter will be referred to the EU for a final decision (see case study of Viagra®). A purely
national procedure intends that the approved product is thought to be marketed in only one MS
and under the condition that the summary of product characteristics (SmPC) has not been
harmonised at the European level. Tracking all Regulatory Intelligence sources, including those
mentioned in section IV, supports following on competitive issues as they cover all phases of the
life cycle of a drug (pre- and post- approval and during drug development). Identification and
utilization of appropriate relevant regulatory data- as well as Competitor data sources for
gathering of respective data with reliable updates of the latter are of importance.
Hereby, effective data transparency of publicly available information sources plays hereby a
crucial role and became objective of e.g. the European Medicines Agency (EMA) through
establishing the new EMA-database “Eudra Vigilance Medicinal Product Database Extended
(EVMPD)” as well as on national level e.g. the German new AMANDA-database.
“Successful RI drives successful global business”
However, governmental and pharmaceutical industry’ initiatives strive for even more and
effective transparency in order to serve the public interest even better. Besides, harmonisation of
data requirements at European level and the circumstances under which they are implemented at
national level, vary widely across the EU. Despite the aspiration for harmonisation and
transparency, unfortunately, implementation in the national law is still a challenge that some of
the EU countries are facing.
Yet, the situation is dynamic and, increasingly, national governments and authorities are making
effort to enable a fully national implementation. Ultimately, they are looking at how self-care and
self-medication can contribute to healthcare.
62
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Hiermit erkläre ich an Eides statt, die Arbeit selbständig verfasst und keine anderen als die
angegebenen Hilfsmittel verwendet zu haben.
Kolmal Musa
