Drug development and Regulations

1. Drug Development And Regulation
Antonio Di Martino
Research School of Chemistry & Applied Biomedical Sciences
Tomsk Polytechnic University
Russia
dimartino@tpu.ru

2. Introduction
 Large multinational pharmaceutical companies have been the dominant force in drug development during the
latter part of the XX and first part of the XXI century
 Companies hold the own research and development divisions responsible for the discovery, non-clinical, and clinical
development of new drugs
 The same company register the medicine, market it and lead its post-marketing development
 This model has been based principally on small (chemical) molecules
 This model has delivered a wide range of novel therapeutics for the diseases and considerable economic benefit for the
companies. However, the same model will not be able to sustain the industry into the future
 The range of potential therapeutics is expanding rapidly (e.g. cell-based therapies, devices incorporating a drug, nucleic
acid-based therapies). Companies face difficulties o get resources or expertise in all the emerging technologies. This is
changing the model of development
 Pharmaceutical companies remain the drivers for large-scale development and marketing of new drugs, but there are
other stakeholders taking part in the process like Universities and other research establishments

3.  Universities and sponsors of research (charities and governments) are increasingly focused on the commercial
applications of research to receive a fair proportion of financial rewards through spin-off companies or licensing
agreements
 Other research establishments are small research companies that often have a single lead drug candidate
 research resource is now increasing due to collaboration between the professional drug developers and
government bodies to deliver solutions that preserve the integrity of the science and clinical development
sharing the costs involved
 The principal targets of the approaches that have delivered the majority of the medicines available today are
encompassed by the concept of a ‘receptor’
 Drug discovery is moving into a different phase which will involve a much greater range of potential targets

4. Empirical chemistry
 One of the most fertile sources of drug development has been that of empirical chemistry
coupled with applied pharmacology
 Iterative modification = changes in the prototype structure to improve its profile,
receptor specificity and adsorption
 Long and difficult process as compounds have to be purified and tested in each step
 Combinatorial chemistry allows a fast production of pool of compounds having
related chemical structure
 Development of suitable systems for testing – overcome the rate-limiting factor

5. Physiology & Pathophysiology
 Understanding of the pathophysiology of disease is the first step for discovering new drugs
 Understanding the role of hormones, neurotransmitters, receptors and
enzymes involved in various illnesses
 Parkinson’s = role of dopamine depletion and dominance of cholinergic transmission
 Hypertension = role of the symphatetic and renin-angiotensin system
 Peptic ulceration = role of H+/K+ exchanger in the generation of acid
 Diabetes = understanding the correlation with the failure of
insulin production or not response

6. 10.1161/CIRCRESAHA.116.303603

7. Medicine Volume 36, Issue 7, July 2008, Pages 369-376

8. Rational Drug Design
 Identification of the drug target and in silico characterization
 Binding site structure construct by crystallographic techniques and computer-aided prediction
 Modelling of the drug-receptor interaction before to synthetize the drug
 Combination of in silico techniques with chemical libraries
 Rate limiting factor is the identification of the targets and the role played in the
pathophysiology

9. Traditional drug development process
Medicine Volume 36, Issue 7, July 2008, Pages 369-376

10. Preclinical Phase
 Preclinical studies are required for a new drug before can be tested on human ( clinical
phase)
 Choice of the species = pathophysiology similar to human
 Toxicology studies performed on rodent and non-rodent to assess
1) the doses associated with toxicity
2) Targets
3) Reversibility of the toxicity
 Studies are required to evaluate the effect of the new compound on
 Fertility
 Reproduction
 Teratogenicity
 Mutagenicity
 Cancerogenicity
 Preclinical studies for biopharmaceutical molecules (e.g. monoclonal antibodies)
They are oriented to understand the biology of the target

11. Phase I – Phase III
Phase I = Healthy volunteers (20-80) First into man studies
Repeated dose studies to establish ADME,
pharmacodynamics properties
Duration : up to 1 year (around 70% of phase I progress to phase II)
Phase II = Patients ( 100-200) Proof of concepts
Investigate effectiveness and dose-response relationship
Determination of the optimal dosing regiment
Duration : 1-2 years (around 33% of phase II progress to phase III)
Phase III = Patients (100-1000s) Efficacy and Safety
Large confirmatory studies to get detailed information on the
effectiveness and safety in the target patient population prior to
submit application to regulatory authorities
Duration : 1-2 years
To provide to regulatory agency: Indication for use – side effects – dosage – drug interactions – contra
indications – warnings – monitoring – patient information

12. Phase IV
 Trials are carried only after a drug has been granted a marketing authorization ( license) by the regulatory body
 Phase IV studies are conducted to
1) Evaluate the use of a drug for new indications to extend the license
2) Test a new formulation. Different kinetic properties may alter the therapeutic effect
3) Address a particular safety concern

13. Novel approach to drug therapy
 Traditional approach = targeting membrane-bound receptors and enzymes with small molecules has been largely investigated
 Modern target = second messenger systems, nucleic acids, cellular networks represent the nowadays challenger
 The range of new approach is very broad with high potential
 The challenges is due to the lack of development science to guide the translation of the molecules to medicine with
a defined benefit-risk profile

14. Pharmacovigilance
 The safety profile of a new drug is unknown when it reaches first the market
 The number of patients exposed to a drug clinical trials to get marketing authorization is relatively
small
 Additional safety studies as required by the regulatory authorities to the company
 Larger in scale event

15. Safety risk
 It represents an issue for all drug treatments
 Toxicological studies – identification of potential risks
 Toxicological studies- understand the biology of the target system
 Rare and potentially serious adverse effects of a medicine may not be identified during in the drug
development phase – small number of people
 Post-marketing safety surveillance (pharmacovigilance)
 Acceptable risk = difficult to establish – it depends on the context and benefits

16. Financial risk
 Financial risk involves the possibility to continue to develop something that is not going to be effective
 Decision making in early development - commonly based on surrogates and biomarkers
 Failure to chose reliable biomarkers can lead to very costly mistakes with apparently impressive phase II
followed by a negative phase III
 Failure in phase III cannot be afford
 Making early decisions about the viability of a new therapy and its eligibility for reimbursement by healthcare systems
 Will be critical in future

17. Patents
 Generally are granted for 20 years from the point of filing early in drug development -
it means max 10 years of market exclusivity for the product
 Patents permits to recoup the costs of R&D and make a profit by selling the branded medicine
 When patent expires price drop due to the generic (non-branded) versions
 Different way to protect the market share after patent expires
( e.g. withdraw the original brand in favor of a new formulation)
 Additional patent protection to stimulate developments

18. European Regulatory System for Medicines

19. The European medicines regulatory system network :
 50 regulatory authorities from the 31 EEA countries
 The European Commission
 EMA
 To ensure high standard regulation for medicines a diversity of expert are involved
 Exchange of knowledge, ideas and best practice between scientists
 EMA and Member States cooperate and share expertise
 Cooperation between Member States reduce duplication, share the workload and ensure an effective and
efficient regulation of medicines across EU
 EU legislation requires that each Member State operates to the same rules and requirements

20. Marketing Authorization
 All medicines must be authorized before they can be placed on the EU market
 Different routes to get authorization
 Centralised procedure
- The marketing of a medicine is allowed on the basis of a single EU-assestement
- Authorization is valid throughout EU
- Pharmaceutical company submit a single authorization application to EMA
CHMP (Committee for Medical Products for Human Use)
CVMP (Committee for Medical Products for Veterinary Use)
Scientific assessment of the application
Provide recommendation to the European Commission
 Use of centrally authorized procedure is compulsory for many innovative medicines, particularly those for rare diseases
 Majority of medicines authorized in EU do not fall in the centralized procedure but are authorized by National Competent
Authorities (NCAs) in the Member State

21. Decentralized Procedure
 Application for the authorization can be made simultaneously in more than EU Member State
 It has not yet been authorized in any EU country
 Does not fall within the scope of centralized procedure
Mutual-Recognition
 A medicine is authorized in one EU Member States
 Application to recognize the authorization in other EU countries
 Rules and requirements applicable to pharmaceuticals are the same in the EU independently from the authorization route
 EPAR ( European Public Assessment Report) = published for every human or veterinary medicine granted or refused
of a marketing authorization following EMA assessment
 Decision regarding price and reimbursement take place at the level of each State Members – in the context of the
national health system of that country

22. The role of EMA (European Medicine Agency)
Established in 1995 to ensure the best use of scientific resources, evaluation,
supervision and pharmacovigilance of medicines across Europe
EMA is responsible for the scientific evaluation of innovative and high-technology
medicines developed by pharmaceutical companies for use in the EU
EMA scientific committees
CHMP = Committee for Medical Products for Human Use
PRAC = Pharmacovigilance Risk Assessment Committee
CMVP = Committee for Medical Products for Veterinary Use
COMP = Committee for Orphan Medicinal Products
HMPC = Committee on Herbal Medicinal Products
PDCO = Paediatric Committee

23. The role of the European Commission
 It grants or refuse, changes or suspends marketing authorization for medicines that have been
submitted via the centralized procedure
 Decision is taken on the basis of the scientific assessments carried out by EMA
 Can take action when harmonized regulatory measures in all MSs are considered necessary to follow
 The EU can take action about:
 Right of initiative = propose new or amended legislation for the pharma sector
 Implementation = adopt implementing measures as well as oversee the correct application of EU law
on pharmaceuticals
 Global outreach = collaboration with relevant international partners and promote EU regulatory system
globally

24. National Competent Authorities (NCAs)
It is responsible for the regulation of human and veterinary medicines in EU
The work is coordinated in a forum called Heads of Medicines Agencies (HMA)
NCAs works closely with EMA and the EU Commission
HMA meets 4 times per year to address key strategic issues for the network and
to streamline mutual recognition and decentralized procedure

25. Guidelines and scientific advice
 EMA prepares scientific guidelines based on the latest thinking on developments in biomedical sciences
 Available to guide the development programmes of medicines developers who wish to submit application for marketing
authorization in EU
 Ensure that medicines are developed consistently and to the highest quality
 Provides product-specific scientific advice to companies for medicine development
 NCAs also can provide scientific advice to companies

26. Authorisation and supervision of manufacturers
 Manufacturers, importers and distributors of medicines in the EU must be licensed before they can carry out those activities
 The regulatory authorities of each Member State are responsible for granting licenses for activities taking within their
territories
 All manufacturing and importing licenses are entered into EudraGMDP
 Manufacturers listed in the application of a medicine to be marketed in the EU are inspected by an EU authority
 Equivalence between Member States’ inspectorates is ensured by including common legislation, common good
manufacturing practice (GMP), common procedures for inspectorates, technical support, meetings, trainings, and internal
and external audits
 To be imported into the EU, an API needs to be accompanied by a Written Confirmation issued by the competent authority of
the country where it is produced, confirming that the good manufacturing practice (GMP) applied is at least equivalent to the
recognised EU GMP standard
 Every batch of medicines must be certified as having been manufactured and tested in accordance with GMP and in
conformance with the marketing authorisation before it can be released onto the market in the EU
 If the product is manufactured outside the EU and has been imported, it needs to undergo full analytical testing in the
EU, unless a mutual recognition agreement (MRA) is in place between the EU and the exporting country.

27. Safety monitoring of medicines
 The European regulatory system for medicines monitors the safety of all medicines that are available on the European market
throughout their life span.
 EMA has a committee dedicated to the safety of medicines for human use — the Pharmacovigilance Risk Assessment Committee, or
PRAC
 If there is a safety issue with a medicine that is authorised in more than one Member State, the same regulatory action is taken
across the EU and patients and healthcare professionals in all Member States are provided with the same guidance
 All suspected side effects that are reported by patients and healthcare professionals must be entered into EudraVigilance
 These data are continuously monitored by EMA and the Member States in order to identify any new safety information
 EMA provides public access to reports of suspected side effects for centrally-authorised medicines in the European database of
suspected drug-reaction reports
 In addition, the EU’s pharmacovigilance legislation enables the PRAC to hold public hearings during safety reviews of medicines if
deemed useful
 Public hearings are intended to support the committee’s decision-making by providing perspectives, knowledge and insights into the
way medicines are used in clinical practice

28. Clinical Trials
 The authorisation and oversight of a clinical trial is the responsibility of the Member State in which the trial is taking
place
 Clinical trials that have been authorised in the EU are tracked by the European Clinical Trials Database (EudraCT)
 It is used by NCAs and clinical-trial sponsors to enter information protocols and results of clinical trials
 A subset of this information is made publicly available by EMA via the EU clinical trials register

29. International cooperation
 The European Commission and EMA, in close cooperation with Member States, work to forge close ties with partner
organisations around the world.
 These activities aim to foster the timely exchange of regulatory and scientific expertise and the development of best
practices in the regulatory field across the world.
 The European Commission and EMA work with the World Health Organization (WHO) on a range of issues, including
medicines intended for markets outside the EU, the quality of medicines and the development of international
nonproprietary names.
 one of the main forums for multilateral international cooperation is the International Council for Harmonisation of
Technical Requirements for Pharmaceuticals for Human Use (ICH), which brings together medicines regulatory
authorities and pharmaceutical industry from around the world.
 The Veterinary International Conference on Harmonisation (VICH) is the equivalent forum for veterinary medicines.
 EMA and many NCAs are also involved in the Pharmaceutical Inspection Convention and the Pharmaceutical Inspection
Co-operation Scheme

30.  Regulatory cooperation and exchange of information with international regulators is also assured through the
International Pharmaceutical Regulators’ Forum (IPRF).
 A strategic forum at the level of global agencies has recently been established — the International Coalition of
Medicines Regulatory Authorities (ICMRA).
 ICMRA is a voluntary, executive level entity of medicines regulatory authorities worldwide providing strategic
coordination, advocacy and leadership.
 There are also a number of bilateral cooperation agreements in place that facilitate the exchange of important
information on medicines between regulators inside and outside the EU.