Master's Thesis, 2004, 39 Pages
1. List of Abbreviations
3. Components of Regulatory Intelligence
3.1 Competitor Information
3.1.1 Criteria for the definition of relevant competitors
3.1.2 Essential information to be gathered about competitors
18.104.22.168 Trade name
22.214.171.124 International Non-proprietary Name (INN)
126.96.36.199 Drug class
188.8.131.52 Type of Procedure
184.108.40.206 Countries and the associated Submission date / Approval date
220.127.116.11 Clinical trials presented in the dossier
18.104.22.168 Competitor labelling
3.1.3 Sources of Competitor Information
22.214.171.124 Authority Homepages
126.96.36.199 Company Homepages
188.8.131.52 Scientific Publications
184.108.40.206 Scientific Internet Search Engines
220.127.116.11 General Internet Search Engines
18.104.22.168 Labelling Databases
3.2 Regulatory Environment
3.2.1 Agency Benchmarks
3.2.2 Regulatory Precedents on Other Products
3.2.3 Ongoing and Future Regulatory Changes
22.214.171.124 Review 2001 (Europe)
126.96.36.199 EU Enlargement
188.8.131.52 Implementation of the Clinical Trial directive (Directive 2001/20/EC)
184.108.40.206 Implementation of the CTD structure for Dossiers
3.2.4 Trade Associations
3.2.5 Regulatory Associations
3.2.7 Training courses and Meetings
3.3 Legal Requirements
3.3.1 General Requirements
220.127.116.11 Supra-national Guidance - Example: ICH
3.3.1 Therapeutic Area Guidance – Example: Microbial Diseases
3.3.2 Special Populations – Example: Paediatric Patients
3.3.3 Orphan Drug Designation
4. Regulatory Strategy
4.1 Definition of “Global Regulatory Strategy”
4.2 Regulatory Affairs Strategic Contributions to the Global Multidisciplinary Development Plan
4.2.1 Competitor Analysis and Target Labelling
4.2.2 Definition of Trade Name and INN
4.2.3 Definition of Key Markets
4.2.4 Definition of a Clinical Development Plan
4.2.5 Identification and Validation of Relevant Guidelines
4.2.6 Life Cycle Management Strategy
4.3 Regulatory Strategy and Impact on other Disciplines
4.3.1 Submission Strategy
4.3.2 Strategy for Meetings with Health Authorities
4.3.3 Issue Management
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Many disciplines claim “intelligence” as part of their business, e.g. marketing intelligence, business intelligence, regulatory intelligence. This document focuses on regulatory intelligence as a pre-requisite of the regulatory strategy for drug development until submission. Drug life cycle management after drug approval as well as aspects of generic drugs are not considered.
Today, there are many drugs for similar indications in the market (e.g. more than 20 beta-blockers for hypertension) and heavy financial constraints press the international health care systems. That means a restricted chance of reimbursement for new drugs in the market place that do not represent a really new therapeutic concept. In addition, increasing regulatory requirements before getting a drug approved by the authorities lead to more expensive programs for drugs under development. For all these reasons, the return-on-investment (ROI) decreases for newly developed drugs and companies no longer have resources, in terms of man power and money for drug research and drug development „by chance“. Innovative, successful and financially reasonable drug research and development (“claims driven research and development”) becomes more and more important. Pressure on the companies regarding „hit rate“ for the transition of development candidates to marketed products and the time to market increases. Companies develop strategies on various levels of management in order to focus on promising projects in promising markets to make optimal use of the available resources and maximise the ROI. The general management defines indications of interest (strategic decision based on business intelligence) that the company is going to focus on. Background for the decision may be the unmet medical need, the potential market size and the resulting potential positive ROI (e.g. positive net present value [NPV] as a basis of calculation). This strategic decision is the rationale for research to focus on these indications. Once, research and basic screening is successfully done, drug development starts. Within this process, Regulatory Affairs takes a key role and supports the process of drug research and development over the entire development cycle.
One of the major Regulatory Affairs contributions to the overall drug development is the regulatory strategy for the development candidate. Regulatory intelligence is the basis for any strategic considerations within the regulatory department. Regulatory intelligence consists of the following key components:
- Competitor Information
- Regulatory Environment
- Legal Requirements.
At the start of drug development, the intelligence work, as part of the regulatory strategy, is initiated and needs to be refined and updated over the entire life cycle of the product including the pre-submission as well as post-submission phases.
Analysis of competitor information is one of the main components of a regulatory strategy. It is very helpful to know which important competitors are in the therapeutic area, the status of the competitive drug (pre-clinical, clinical phase, launched, where launched, post-approval commitments, ...), etc. There are various data sources of very different quality available depending on the region / country and product class of interest. Competitors evaluated should cover all stages of development. Of course, the contribution of Regulatory Affairs is greater in later stages of the drug development (e.g. little contribution to compounds in research, major contribution to compounds already registered).
The relevant competitors are usually defined in close co-operation with other disciplines. Important disciplines in this regard are the Medical and Marketing Departments. The Medical Department provides unique insights on the medical needs in the community, the “gold standard of therapy” for the target indication in the target region / country (e.g. inhaled glucocorticosteroids at higher doses plus a long acting inhaled b2-agonist twice daily for severe persistent asthma ). The Marketing department's contributions are more oriented towards market share of drugs already available in the market place, expected market share of drugs under development, market size, financial power of the market. Regulatory aspects for the choice of a competitor for analysis are mainly:
- Same area of indication
- Same mode of application (e.g. most recent approvals of Dry Powder Inhalers [DPIs])
- Pharmacovigilance aspects (e.g. other drugs with QT prolongation in case the development candidate shows QT effects)
- Recent launches in the target regions / countries
- Subjects of advisory board meetings
- Recent Market Authorisation withdrawals / rejections
- Subjects to interesting special subgroups like orphan drug status or paediatric development programs
Competitor analyses are done from various perspectives and by various disciplines in order to achieve a comprehensive picture about the competitive situation for a certain indication in the target regions / countries. The ultimate goal is to learn from other companies’ experiences in terms of success and failures of their drug development.
Trade names can be different in different regions and countries. The assignment of a trade name depends on cultural and linguistic habits. In addition to this, trade names need to be distinguishable from similar trade names in the country in order to avoid confusion in the pharmacies. Therefore, it is essential to have an overview on existing trade names in the target region / country. If a company aims for one global trade name this name needs to be acceptable to all target countries with their national languages. If the name sounds acceptable for English speaking countries it may have an unacceptable meaning in other languages. An example is the Mitsubishi car “Pajero” which is acceptable in English but means a strong insult in Spanish. So, the overview on already existing trade names is a basis to think about potential own trade names.
The WHO (http://www.who.int/medicines/organization/qsm/activities/qualityassurance/inn/ orginn.shtml) has a constitutional mandate to develop, establish and promote international standards with respect to biological, pharmaceutical and similar products. In this context, the WHO is responsible for the approval procedure of INNs. Each INN is a unique name which is globally recognised and public property. It facilitates the identification of pharmaceutical substances or active pharmaceutical ingredients. The general idea is to have identical prefixes or suffixes for one drug class (e.g. –bactam for beta-lactamase inhibitors, gli- for sulfonamide hypoglcaemics) , , . The rest of the INN can be chosen by the applicant, and of course this provides an opportunity to “burn” the INN into the customer’s mind. On the other hand, after the end of the patent / data protection period generic companies will enter the market place and may use the INN as part of their brand name (e.g. ASS Ratiopharm). The INN being “burned” into people´s minds would be a disadvantage for the originator once generic competitors enter the market place. Therefore, the choice of the INN is important, and an overview on the competitor situation helps in terms of positioning their own product.
The drug class of a competitor is important in order assess the market situation and to get a link to the associated ATC code (http://www.whocc.no/atcddd/). The ATC code is assigned by the WHO in order to reflect the major properties of a compound. In the Anatomical Therapeutic Chemical (ATC) classification system, the drugs are divided into different groups according to the organ or system on which they act and their chemical, pharmacological and therapeutic properties.
Drugs are classified in groups at five different levels. The drugs belong to one of fourteen main groups (1st level), with one pharmacological/therapeutic subgroup (2nd level). The 3rd and 4th levels are chemical/pharmacological/therapeutic subgroups and the 5th level is the chemical substance. The 2nd, 3rd and 4th levels are often used to identify pharmacological subgroups.
In various countries, the ATC code assigned to a drug is important for reimbursement by the respective health care system once the drug is approved by the Health Authority. Therefore, it is important to think about the “strategy” to apply for a certain ATC code: can the WHO be convinced that this drug under discussion is the first representative of a new drug class (e.g. in the area of antibiotics) and therefore is suitable for reimbursement? Is the drug under discussion the first member of a new antibiotic subclass (e.g. Penems) and therefore suitable for reimbursement? In various European countries, the third level of the ATC code is regarded as the “magic limit” to define new and reimbursable drugs.
Proposed new ATC codes are published in print (WHO Drug Information Journal and WHO Pharmaceutical Newsletter) and in the Internet (www.whocc.nmd.no) and interested parties are allowed a deadline (period not specified) to comment / object. With no objections received, the new ATC code will be considered final.
Another similar, but independent classification system, is the EPhMRA (European Pharmaceutical Market Research Association) classification (http://www.ephmra.org/site_map.html). The EPhMRA is used world-wide e.g. by IMS (Institute for Medical Statistics) for market research statistics within the pharmaceutical industry. Often, the company internal marketing analysis is based on IMS data. An important point to note about the EPhMRA system is that products are classified, not molecules. "Product" is defined as a pack or unit that can be dispensed, prescribed, etc. The products are classified according to their main therapeutic indication. Each product is assigned to one category. There is no apportionment of sales by usage, such as diagnosis value.
In the 1970s, WHO adapted the EPhMRA system for its own needs. This became the system that the WHO calls the Anatomical Therapeutic Chemical system (ATC). At the present time, the two systems are similar but are designed to meet two different goals. The purpose of the WHO ATC is to meet the needs of teaching, clinical trials, health organisations, and governments. The EPhMRA Anatomical Classification system must meet the needs of marketing research and marketing. The WHO ATC classifies substances while the EPhMRA/PBIRG Anatomical Classification system classifies products.
This aspect is mainly relevant for Europe. In Europe, three major types of approval procedures can be distinguished: the centralised procedure, the Mutual Recognition Procedure (MRP) and the purely national procedure (possible only in case of "one-country-submissions"). Each of the procedures has certain advantages and disadvantages.
The centralised procedure for authorising biotechnology-derived (mandatory) and highly innovative (by choice) medicines is laid down in Council Regulation (EEC) No 2309/93 . The centralised procedure, which came into operation in 1995, allows applicants to obtain a marketing authorisation that is valid throughout the EU. When a company wishes to place a medicinal product that is eligible for the centralised procedure on the market, it submits an application directly to the EMEA (European Agency for the Evaluation of Medicinal Products), to be assessed by the Committee for Proprietary Medicinal Products (CPMP). Once the evaluation is completed, the CPMP gives a favourable or unfavourable opinion as to whether to grant the authorisation or not. The time limit for the evaluation procedure is 210 days, and the various steps during these 210 days are clearly defined. The Agency then has 30 days to forward its opinion to the Commission. This is the start of the second phase of the procedure: the decision-making process. The Agency sends its opinion to the Pharmaceutical Unit in the eleven Community languages, with annexes containing:
- The summary of product characteristics
- The particulars of the manufacturing authorisation holder responsible for batch release
- The particulars of and the manufacturer of the biological active substance and
- The conditions of the marketing authorisation
- The labelling and the package leaflet.
During the decision-making process, the Commission services check marketing authorisation compliance with Community law and turn the Agency opinion into a binding decision for all the Member States. The Commission has 30 days to prepare a draft decision. The medicinal product is assigned to a Community registration number, which will be placed on its packaging if the marketing authorisation is granted. During this period, various Commission directorates-general are consulted on the draft marketing authorisation decision. They have 10 days to deliver their opinions  (http://pharmacos.eudra.org/F2/pharmacos/docs/brochure/pharmaeu.pdf). Centrally-authorised products may be marketed in all Member States.
Arrangements for implementing the mutual recognition procedure are laid down in Council Directive 2001/83/EC . To be eligible for this procedure, a medicinal product must already have been authorised for marketing in one Member State. Since 1 January 1998, the mutual recognition procedure has been compulsory for all medicinal products to be marketed in a Member State other than that in which they were first authorised. Any national marketing authorisation granted by an EU Member State’s national authority can be used to support an application for its mutual recognition by other Member States. The mutual recognition procedure works on the principle of the mutual recognition by EU Member States of their respective national marketing authorisations. An application for recognition may be addressed to one or more Member States. The applications submitted must be identical and all concerned Member States must be notified. The first country that evaluates the medicinal product via national procedure becomes the “Reference Member State” (RMS). It notifies this decision to other Member States (“Concerned Member States” [CMS]), to whom applications have also been submitted. CMS may then suspend their own evaluations, and await the RMS’s detailed assessment report on the product. As soon as the assessment is completed, copies of this report are sent to all Member States and they then have 90 days to recognise the decision of the RMS and the SmPC as approved (by granting a marketing authorisations with identical SmPCs). In case any CMS refuses to recognise the original RMS national authorisation, e.g. on public health reasons, the reasons are submitted to the appropriate EMEA scientific committee (CPMP), for arbitration. The EMEA committee opinion is then forwarded to the Commission, for the start of the decision making process. As in the centralised procedure, this process entails consulting various Commission directorates-general and the regulatory standing committees on human medicinal products, as appropriate. Once the Commission decision is taken, it is binding for all the Member States concerned, which must withdraw, grant, or vary the marketing authorisations as necessary to comply with the decision. Other Member States not directly concerned at the time of the decision are also bound as soon as they receive a marketing authorisation application for the same product. In the event of a serious disagreement among Member States, which makes it impossible for the Commission to decide, a decision may be taken by the Council of the European Union . The MRP can be repeated in order to include Member States that have not participated in the “first wave” of applications (repeat use of MRP).
A purely national application within the EU is only possible if the product under discussion is designated for being launched in one country only. This approach today is unusual as drug development usually does not focus on one single country. This purely national approach needs to be differenciated from the MRP approach that has the national approval in the RMS as a pre-requisite.
Another differenciation of dossiers is “original dossier” and “line extension” (Europe) or sNDA (USA) (supplemental NDA).
This thesis only covers new medical or chemical entities until submission; generic applications as well as medical devices are excluded. Therefore, aNDA (abbreviated applications), sNDA etc. are not considered, only the submission of "original" dossiers.
The overview of submission dates per country is an important source of information in order to get an idea about the competitor’s submission strategy as well as authority driven hurdles. Example: if the competitor launched an antibiotic drug first in the USA, then in Germany and after Germany in Italy, Spain and Portugal at the same time and after that in many Asian countries the conclusion may be that the USA is the most important market for the company and FDA the most relevant authority that shows the way to future approvals in other countries. In Europe, the company probably chose a MRP with Germany as reference member state. As there are only “smaller” CMS (in terms of sales), there certainly is an issue in the dossier that led the company to the decision of not submitting (or withdrawing the dossier) in countries like France that represents a huge European antibiotic market and a very “difficult to handle” authority. After Europe, other markets have been discovered and entered. This conclusion can become relevant when developing the own submission strategy.
If in Europe a specific country shows up frequently as RMS or rapporteur for a specific drug class one may conclude that this agency has a certain experience in this indication area. Recent submissions in a country are a good hint for up-to-date knowledge of the agency for a specific area of indication. The delay between submission date (if accessible) and approval date gives an idea about the approval time in this country.
Clinical trials are an excellent source of competitive information as they are designed to reflect the future treatment situation / intention / positioning in the market. Most relevant pieces of information for analysis are the following:
- Inclusion / Exclusion criteria
- Therapeutic regimen (first line, second line, ...)
- Trial design:
- Controlled / uncontrolled trials
- Parallel groups / crossover design
- Number of treatment arms / crossover phases
- Co-medication (if relevant)
- Number of patients
- Countries involved
- Clinical endpoints
- Interactions with other drugs / food
- Studies in special populations, e.g.:
- Hepatic / renal dysfunction
- Elderly / paediatric patients / pregnant women
- Clinical trials initiated due to a post-approval commitment
For details refer to ICH guidance documents E6, E8, E10 (http://www.ich.org/UrlGrpServer.jser?@_ID=276&@_TEMPLATE=254).
In case the competitive compound is already in the market place, the approved SmPC / PI is absolutely helpful and allows comparisons between products in a country and between countries for one specific product. An interesting finding may be the non-mentioning of gonorrhoea for an antibiotic drug, and the explanation can be “not approved due to insufficient data” but may also be covered by the more general indication of “urinary tract infections”. There may be countries with more explicit indications in their labelling (e.g. USA) and others with less explicit indications (e.g. Spain) which does not at all reflect properties of the product under evaluation but just country specific attitudes. These two aspects need to be distinguished from each other when evaluating national SmPCs. The differences between countries also need to be reflected when the appropriate European procedure is selected (MRP with RMS / CMSs, centralised procedure with rapporteur / co-rapporteur). In addition to the already mentioned national differences, one needs to keep in mind the regional difference, e.g. the US labelling is very different from the European SmPCs / PIs in terms of presentation and level of detail, and in the USA the patient information leaflet often is not provided to the patients (e.g. number of leaflets attached to the bottle insufficient or pharmacist does not print the patient related information out).
In this section very few agency homepages are presented as examples for the type of information to be gathered from agency homepages.
The FDA homepage (www.fda.gov) is very helpful. One “room” within this homepage is the "Center for Drug Evaluation and Research" (CDER) (www.fda.gov/cder) which is dedicated to human drugs. The orange book (one link from the CDER homepage) contains all approved drug products in the USA and allows access to basic patent data, mainly patent number and patent expiration as well as basic information about the drug itself (applicant, approval date, ...). The link to “Drug Approvals” allows access to important information (Product name, Company, Application number, Approval Date, Letter Posted, Label Posted, Review Posted). In the optimal case, all these categories contain attached PDF-files. If these files are not posted the Summary Basis of Approval (SBA) can be requested from the FDA as paper copy. The information provided by the FDA is comprehensive and allows detailed conclusions about documentation provided to the FDA, the strengths and weaknesses of the dossier and that leads to “lessons learned” for the own development candidate. The National code directory (http://www.fda.gov/cder/ndc/database/ default.htm) also provides brief tabulated information about the drug under discussion. Rationale for the provision of all the key information to the interested public is the “Freedom of Information Act” (FOI).
The FDA Advisory Committee homepage
(www.fdaadvisorycommittee.com/FDC/AdvisoryCommittee/TOC.htm) provides alerts about the future sessions and results of the past advisory board meetings. The newsletter service can be ordered for free and keeps the Regulatory Affairs Manager always up-to-date with regard to the topics currently under discussion within the FDA. Given the appropriate IT equipment one is able to participate in the meetings via webcast. This allows even better information as one sees interactions between the meeting participants.
The MedWatch (www.fda.gov/medwatch/SAFETY/2002/safety02.htm#premar) represents the FDA safety information and adverse event reporting program and is a sound source of information about product-related and class-related safety issues. MedWatch also offers an E-mail alerting service for free.
The European Public Assessment Report (EPAR) (http://www.emea.eu.int/htms/human/epar/ epar.htm#) reflects the scientific conclusion reached by the Committee for Proprietary Medicinal Products (CPMP) at the end of the centralised evaluation process and provides a summary of the reasons for the CPMP opinion in favour or not in favour of granting a marketing authorisation for a specific medicinal product. It is made available by the EMEA (http://www.emea.eu.int) for information to the public, after deletion of commercially confidential information. The legal basis for its creation and availability is contained in Article 12 (4) of Council Regulation (EEC) No. 2309/93 . The EPAR is a concise document which highlights the main parts of the CPMP scientific discussion leading to the CPMP opinion. The content of the EPAR is derived from the various reports produced during the centralised evaluation procedure, resulting from the review of the documentation submitted by the applicant, together with the scientific discussion at CPMP meetings. The EPAR is updated throughout the authorisation period as changes to the original terms and conditions of the authorisation (i.e. variations, pharmacovigilance issues, specific obligations) are made. The abstract, authorised presentations and the Commission Decision product information of all presentations are provided in all EU languages. The scientific discussion and procedural steps are available in English only.
The MRI Product Index (http://mri.medagencies.com/prodidx/) includes medicines approved in the Member States of the European Union according to the procedure for Mutual Recognition. The MRI contains at least information about RMS, CMSs, Marketing Authorisation Holder (MAH), MR-number, day 90 (for details see section 18.104.22.168). The more recent entries do also contain a link to the SmPC approved. If some of the information is missing, the solution would be to contact the RMS and ask for that piece of information.
The EMEA Web Site Map (http://www.emea.eu.int/sitemap.htm) links to various sections of the EMEA where interesting competitor information can be gathered (e.g. marketing authorisation withdrawals, press releases, referrals, pharmacovigilance opinions).
The “Heads of Agencies” homepage (http://heads.medagencies.org/) links to the Health Agencies of all countries within the EU. Relevant national information as press releases and pharmacovigilance information can be picked up. Some agencies like the French L’Agence française de sécurité sanitaire des produits de santé (Afssaps) present their homepages in the national language only, other agencies like the Swedish Medicinal Products Agency (MPA) provide an English version of their homepage.
There are three Japanese Regulatory Authorities. One part of the “Ministry of Labor, Health and Welfare” (MLHW, Kosei Roudou Syo) is the Pharmaceutical and Medical Safety Bureau (PMSB) which finally approves a product. The Pharmaceuticals and Medical Devices Evaluation Center (PMDEC, Sinsa Senta) (http://www.mhlw.go.jp/english/) is part of the National Institute of Health Services (NIHS) and provides the evaluation of all dossiers (quality, efficacy and safety) for all prescription drugs and medical devices as well as proprietary drugs, quasi-drugs and cosmetics via an evaluation team. The Organisation for Pharmaceutical Safety and Research (OPSR, KIKO) provides consultation services to pharmaceutical companies (scientific advice), reviews the IND documents and checks GxP (Good Practice in different areas [symbolised by the x]) compliance.
Some of the URLs related to the Pharmaceuticals and Medical Devices Evaluation Center are provided in English, most of them are only available in Japanese language.
In case the focus is on a specific product from a specific company one can access the company’s homepage and gather information from there. Besides mainly product-related information (e.g. successful approval of product XYZ, the “top 10 products” of the company, overview of company’s products), the companies’ annual reports as well as the information sent out to shareholders and the agenda for the shareholder meetings are valuable sources of information.
Scientific publications can be obtained from journals like e.g. "British Medical Journal" (http://bmj.bmjjournals.com/). Many of these journals provide electronic versions that are accessible via the Internet. Focus of information gathered from these sources are published results of clinical studies, research results with new compounds, toxicological studies with compounds under development etc..
DIMDI (Deutsches Institut für Medizinische Dokumnetation und Information) (http://www.dimdi.de/de/db/index.htm) in Germany provides free of charge access to various scientific databases, including Medline and Cancerlit (Somed of limited relevance). Medline is one of the best known scientific databases in the medical field. Choosing appropriate search strategies, most of the medically relevant publications can be found in this database amongst them results of clinical studies in the area of indication under evaluation. If the number of patients within a trial is really huge and one product is an investigational product one might think about pivotal phase III trials necessary for a submission. The publication then is an essential source of information regarding study design and results.
Regulatory Affairs journals like RAJ (http://www.pjbpubs.com/cms.asp?pageid=875) provide information about Regulatory Affairs topics currently under discussion and potential regulations coming up in the mid-term future which might be important for the submission of the development candidate.
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