/  Part IV.1 – Regulatory Considerations for Drug Development



Regulatory Considerations for Drug Development

Christiane Chène PhD and Hendrik Tevaearai MD EMBA

A. Introduction

The pathway from discovery to marketing of a new medicinal product is highly regulated. The aim of this chapter is to provide an overview of the regulatory considerations and planning that should be taken into account during drug development.

Regulatory interactions take place throughout development. Planning is highly recommended during all stages of drug development, with frequent reviews of manufacturing and non-clinical and clinical data, in order to minimize the risks and costs involved throughout the process. Regulatory obligations continue following placement of a product on the market. Finally, regulatory requirements are necessary if changes are made to the license.

B. International Conference on Harmonization (ICH) Guidelines

Drug development is regulated by the international Conference on Harmonization (ICH) of Technical Requirements for the Registration of Pharmaceuticals for Human Use, a unique harmonization project involving the regulators and research-based industries of the United States, the European Union and Japan. Started in 1990, the objective of the ICH is to improve efficiencies in new drug development and registration processes. Additional objectives are to promote public health, prevent duplication of clinical trials in humans, and to minimize the use of animal testing without compromising safety and effectiveness. These objectives have been accomplished through the development and implementation of harmonized guidelines. These guidelines, (more than 50 are available today), cover many scientific and regulatory aspects of manufacturing, non-clinical and clinical testing of medicinal products. They are often specific to particular therapeutic indications or type of product, and allow controls early in the development program. For example, several scientific or therapeutic area guidelines on the clinical safety and efficacy of medicines used in conditions affecting the heart and blood vessels are available. Guideline E12 outlines the principles for clinical evaluation of new antihypertensive drugs (1). Guideline E14 provides recommendations to sponsors concerning the design, conduct, analysis, and interpretation of clinical studies to assess the potential of a drug to delay cardiac repolarization (2). These and other guidelines or guidance documents allow the generation of clinical information considered relevant in obtaining marketing authorization by regulatory agencies. Guidelines are not legally binding. These guidelines do, however, represent the agencies’ current approach towards particular topics and deviations must be justified by the applicant. Therefore, it is recommended to take note of these guidelines and to use the information provided for defining and designing studies that will be performed in order to move through development.

C. Scientific Advice

Scientific advice with regulatory agencies

Following consultation of the available regulatory guidance, pharmaceutical companies may have further questions regarding their proposed manufacturing process, pre-clinical dossier package and initial clinical trial designs and seek input on product development plans that would better address the regulatory agencies’ informational needs and thereby increase the probability of marketing authorization. This is particularly important for novel types of products, for which early dialogues with authorities can eliminate expensive and time-consuming studies not considered to be relevant.

In the EU, scientific advice can be obtained from a national agency, for example BfarM in Germany, MHRA in the UK, or MPA in Sweden. In the US, advice is provided by the FDA. Obtaining advice is possible at any time during development or post-authorization for example regarding manufacturing issues, new methodologies, non-clinical studies, design of clinical trials etc.

If the company is planning to develop their medicines for more than one region, scientific advice should be coordinated with advice sought in other regions. This is recommended, at the latest, at the end of Phase II and prior to the initiation of Phase III studies. It should also be noted that in Europe, in addition to scientific advice from national authorities, an EU-wide opinion can be obtained via the European Medicines Agency (EMA). In this case, the advice represents a consolidated opinion from all member states of the EU. EMA advice should be requested for medicines derived from biotechnology processes, for advanced therapy medicines or if the medicinal product is developed for therapeutic indications such as AIDS, cancer, diabetes, neurogenerative disorders, viral diseases or auto-immune diseases falling under the scope of the centralized procedure for marketing authorization.

For questions regarding pediatric development (pediatric investigational plan, PIP) or the development of orphan drugs, EMA is also the agency to be approached. In addition, the sponsor may obtain advice from EMA and FDA in parallel, to have further scientific input from both agencies. In general, advice from an agency is not binding, on the part of the agency or the company, but deviations from the given advice must be justified.

Scientific advice with health technology assessment (HTA) authorities

In addition to regulatory authorities, Health Technology Assessment (HTA), or reimbursement bodies, have recently been initiated in the EU to provide country-specific interactions regarding clinical and pharmacoeconomic aspects possibly influencing the likelihood of a positive reimbursement decision upon marketing approval. It could well be that new medicines authorized by the European Commission or a single EU country are ultimately not reimbursed and/or used because they fail to match the requirements of HTA bodies.

From an HTA perspective, the UK-specific National Institute for Clinical Excellence (NICE) scientific advice procedure is probably the best recognized approach, and has been utilized by a number of manufacturers interested in confirming which clinical and economic data will be needed for the UK market. In Germany, the joint body Federal Joint Committee/ Institute for Quality and Efficiency in Health Care (GBA/IQWIG) is the respective HTA agency concerned with the price setting procedure for new drugs. Exchange of information with these or other national HTA authorities is therefore increasingly recognized as being of high importance for the pharmaceutical industry. At present, no comparable framework exists in the US.

In order to facilitate early dialogue between regulatory authorities, HTA bodies and drug developers, the EMA has recently published a draft of best practice guidance for industry on parallel scientific advice with HTA agencies (3). Such joint scientific EMA/HTA advice is one of the potential mechanisms by which manufacturers can obtain perspectives from both regulatory and HTA agencies, in order to further support drug development and the value proposition.

D. Regulatory Considerations During Non-Clinical Development

Discovery research

This initial phase of development covers the period from target identification to nomination of potential candidates for a drug development program. It may be initiated to perform preliminary safety and formulation tests, or to confirm the pharmacological mode of action with regard to potency and selectivity. It covers the identification of potential biomarkers, preliminary pharmacokinetics studies, or the demonstration of activity in in vivo and/or in vitro models. There are no formal regulatory requirements for scientific research in disease models. In general, these studies are not submitted as part of the marketing authorization application. Guidance for this type of investigation is provided by ISO 9000 (4), ISO 17005 (5), Human Tissue Authority (6), or WHO Guidance for QPBR (7).

Non-clinical testing

At this stage of development, research must fulfill the requirements of the non-clinical safety section of the common technical document (CTD) according to Guidance ICH M4S (8). Safety evaluation of candidate investigational products (new chemical entities and biologics) must be conducted according Good Laboratory Practice (GLP).

Several non-clinical ICH guidelines relevant for drug development are available for the identification of pharmacological properties (mode of action and activity in animal models of the disease), pharmacokinetic properties (absorption, distribution, metabolism, and excretion) and toxicological properties of medicinal products. They are important in establishing a safe initial dose level for humans, identifying target organs, determining dose-dependence of toxic effects and providing information on specific toxicity (e.g. genotoxicity, carcinogenicity, or reproduction toxicity) (9). Pharmacodynamic and safety pharmacology studies are defined in ICH S7A. The core battery of safety pharmacology studies includes the assessment of effects on cardiovascular, central nervous and respiratory systems, and should generally be conducted before human exposure, in accordance with ICH S7A and ICH S7B. The latter provides guidance on the non-clinical testing strategy for assessing the liability of QT interval prolongation, which is the single most important cause of drug withdrawals in recent years.

Guideline “ICH topic M3 (R2), Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals, December 2009″ (10) in its most recent version explains in detail which non-clinical studies must be provided for a clinical trial application (CTA) or for a marketing authorization application (MAA in the EU, NDA in the US) of a novel type of product. As for these products, for which human experience with a comparable medicinal product is not yet available to replace lacking non-clinical data, the whole set of non-clinical data listed in ICH topic M3 (R2) must be provided.

E. Regulatory Considerations During Clinical Development

Following completion of relevant non-clinical studies and finalization of clinical trial designs, approval must be obtained from the relevant authority before initiation of first human trials can begin. This involves filing an Investigational New Drug (IND) application in the US, and a national CTA in the EU, for those countries in which the study is to be conducted.

For approval of clinical trial applications, agencies request “adequate information about the pharmacological and toxicological studies of the drug involving laboratory animals or in vitro systems, on the basis of which the sponsor has concluded that it is reasonably safe to conduct the proposed investigations…” (FDA, IND application). All clinical studies need to be conducted according to Good Clinical Practice (GCP) as defined in Guideline ICH E6(R1).

Furthermore, the quality of drug substance and drug product used in clinical studies must be assured. This has to be demonstrated by providing data that support the purity, identity and stability of bulk drug and formulated drug substance. In the EU, GMP requires that all clinical material must be manufactured in accordance with the requirements of GMP Guideline Part I Annex 13 (drug product) and ICH Q7 GMP Guideline Part II (drug substance). This means that there is not much difference in the various GMP requirements for commercial products and products used in clinical trials. In the US, however, FDA issued a final rule exempting most Phase I clinical material from GMP regulations (11). Only for compounds that are already used in Phase II or Phase III studies, or compounds that are already marketed, must the clinical material be manufactured following GMP regulations. But for a first Phase I trial, the sponsor does not need to follow full GMP regulations, although a certain standard of GMP is required in that manufacture.

Phase I studies

Phase I studies are an initial assessment of safety, drug tolerability, and dose range in humans. They usually involve small populations of 10-80 healthy subjects or, in certain cases, patients who receive single or multiple administrations of the investigational drug. The final objective of Phase I clinical studies is to determine the maximum-tolerated dose (MTD) and to provide an initial description of adverse events associated with agent administration in a dose-dependent fashion. Through the characterization of initial pharmacodynamic and pharmacokinetic parameters, Phase I studies enable the design of well-controlled, scientifically valid, Phase II studies and, therefore, form the basis for a cohesive clinical trial program. Phase I studies may also include studies of drug metabolism, structure-activity relationships, and mechanism of action in humans.

The sponsor must provide in vitro and in vivo pharmacology studies to support the rationale for the intended use, and toxicology studies to support the starting dose and duration of a Phase I study. Evaluation of efficacy is generally not the objective of a Phase I trial. Therefore, it is not necessary to restrict the study to a patient population that is homogeneous with respect to disease, or even to restrict it to patients with measurable disease. It is, however, important to exclude patients with impaired organ function who may be more prone to serious toxicity.

Phase II studies

Phase II studies are an initial assessment of efficacy (proof of concept) for a particular indication and in patients with a specific disease, and are conducted to further evaluate safety of the drug under development.

The ultimate goal is to identify efficacy endpoints and dose regimens for pivotal Phase III studies. This usually begins with Phase IIa clinical studies, which are conducted to obtain an initial proof of concept. Phase IIb studies are typically larger, well-controlled, and closely monitored, and may use comparator agents and broader dosages to obtain a much more robust proof of concept. Phase II studies are conducted in a relatively small number patients (100 -300) who have the indicated disease or condition, and may last from several months to a few years.

Phase III studies

Phase III studies are in general well-controlled trials performed to verify efficacy, establish safety, and establish the optimum dosage. They involve a larger number of patients (500-2000). The objective is to provide sufficient data to convince regulatory agencies of the favorable benefit/risk relationship of the medicinal drug under investigation.


Endpoint selection is a critically important step in clinical trial design. It poses major challenges for investigators, regulators, and study sponsors, and carries important clinical and practical implications for physicians and patients. Selection of endpoints of a clinical trial must take into account the need to obtain the information of highest therapeutic interest with the least risk and discomfort for the patient. Consequently, pivotal Phase III trials of new therapies must demonstrate clinically relevant improvement in a clinical end point to justify regulatory approval and clinical use (Allen et al 2009) (12).

The endpoints are also central to the objective of the study and must represent the most effective ways to assess pharmacological responses. In Phase III studies, primary endpoints measure outcomes that will answer the main question being asked by a trial, such as whether a new treatment is better at preventing disease-related death than the standard therapy. In this case, the primary endpoint would be based on the occurrence of disease-related deaths during the duration of the trial. Secondary endpoints are directed toward other relevant questions about the same study; for example, whether there is also a reduction in disease measures other than death, or whether the new treatment reduces the overall cost of treating patients.

Numerous scientific guidelines on the clinical safety and efficacy of medicines used in conditions affecting the heart and blood vessels are available and provide guidance on possible clinical endpoints to be selected for clinical studies (13). These include indications for hypertension, lipid disorders, pulmonary arterial hypertension, arrhythmias, venous thromboembolism, coronary artery disease, and heart failure.

In general, a primary endpoint based on one single outcome is recommended in the regular guidance on study design. However, many recent large trials have chosen a primary composite endpoint consisting of a combination of multiple outcome measures. An endpoint can also be the time taken for an event to occur. For such an endpoint, the events of interest for which a time is to be recorded—such as stroke or heart attack—must be predefined.

The majority of clinical trials for cardiovascular disorders employ surrogate endpoints and clinical biomarkers as substitutes for clinical outcomes. These include measurement of lipid level parameters, such as Low Density Lipoprotein-Cholesterol (LDL-C), High Density Lipoprotein-Cholesterol (HDL-C), and Total Cholesterol (TC), or of troponin, a marker of myocardial cytotoxicity. Regulatory authorities accept the argument that these biomarkers are very closely linked to clinical outcomes, and that they can be considered as valid primary variables in pivotal clinical trials, acting as substitutes for a hard clinical endpoints during the marketing authorization process.

Finally, study endpoints can also be a socioeconomic parameter such as quality-of-life, an endpoint frequently requested by HTA authorities to demonstrate that a new drug provides additional economic benefit compared to standard practice.

F. Considerations Regarding the Pediatric Population

Historically, only very few medical drugs have been tested in clinical trials involving pediatric patients and most of the marketed authorized drugs have been declared as not indicated for use in children. In the absence of alternatives, they have been prescribed basically off-label to this population category, without adequate understanding of specific safety or efficacy aspects and without information regarding the appropriate dose (14). This frequently resulted in unacceptable risks, such as under- or over-dosing of inappropriate formulations. Therefore, during the last years, both FDA and EMA reinforced their commitment to promote better medicines for children and established a complex network of incentives and regulatory requirements for pediatric drug development (15,16).

In the EU, based on Regulation (EC) 1901/2006 (17) “Medicinal Products for Pediatric Use”, pharmaceutical companies that submit an application for marketing authorization of a medicinal product, an extension of indication, a new route of administration, or a new pharmaceutical form of a medicinal product already authorized in the EU, must provide an approved Pediatric Investigation Plan (PIP) and the clinical data as defined therein. The PIP must be agreed upon by the pediatric committee (PDCO) of EMA and is the basis for the development and authorization of a medicinal product for the different pediatric age groups as defined in ICH Guideline E11 (18) (see Table 1).

Table 1. Classification of pediatric age groups (ICH E11)

table 1

The PIP includes details of the timing and the measures proposed to demonstrate quality, safety, and efficacy of the drug in the pediatric population including deferrals until completion of studies in adults. This is to ensure that studies in children are conducted only when the treatment is considered safe. A waiver is granted if the drug is likely to be ineffective or unsafe in part or all of the pediatric population, if it is intended for a condition that occurs in adults only (e.g. breast carcinoma or Alzheimer’s disease), or if it does not represent a significant therapeutic benefit over existing treatments for pediatric patients. Detailed information about the PIP procedure including a guideline on PIP format and content is provided on the EMA homepage (19).

In the US, similar elements and considerations are covered by the Pediatric Research Equity Act (PREA) and the Best Pharmaceuticals for Children Act (BPCA).

In recent years, the FDA and the EMA have released several specific regulatory guidelines for pediatric drug development, forming the regulatory framework for the pharmaceutical industry (e.g. 17,20,21). These guidelines cover various aspects of the design of pediatric studies (e.g. age categories, dose finding, PK sampling, pediatric formulation). They support pharmaceutical companies in their pediatric strategy, which is highly dependent upon the properties of the drug, the disease and the pediatric population. Recommended by many regulatory guidelines (17,20) and endorsed by the authorities, modeling and simulation techniques are well-established approaches in pediatric drug development and aim to support dose identification and aid in study design, and to minimize distress and fear by reducing the number of pediatric patients, as well as the number of samples to be taken from each patient, included in clinical studies (22).

Nevertheless, despite the availability of guidance, pediatric development remains a complex area and close collaboration and communication between pharmaceutical companies and regulatory authorities is essential.

G. Post-Marketing Surveillance

Despite rigorous drug approval processes, more than half of the marketed drugs have serious adverse effects that are not detected during the pre-marketing clinical Phase I to Phase III studies. Therefore, phase IV post-marketing surveillance studies, conducted after approval to market has been granted by regulatory agencies, are required to collect and report data about medicinal drugs once they are used in daily clinical practice (23). As post-marketing surveillance provides the opportunity to assess drug’s safety in every day clinical conditions and in a much greater patient population than in clinical trials, it is a useful tool to detect signals for adverse effects with an incidence of less than 1:10,000. In general, pharmacovigilance information on the safety of a medicinal drug must be provided in Periodic Safety Update reports (PSURs) that are filed at regular intervals.

In the US, post-marketing surveillance is under the responsibility of the FDA. In the EU, the EMA coordinates all pharmacovigilance and post-marketing activities, such as reporting of adverse events. In both regions, post-marketing surveillance is a continuous process of evaluation accompanied by steps to improve drug safety that involves pharmaceutical companies, regulatory authorities, healthcare providers, and patients.

Post-approval surveillance studies are thus a very important part of the pharmacovigilance system. They are designed to confirm the safety of the medicinal product in large patient populations and involve adverse event reporting by physicians. Post-marketing studies may be designed as open studies where the selection of patients is not strictly defined by stringent inclusion and exclusion criteria, but governed by the permissible indications and contraindications of the drug as stated in the prescribing information. This ensures that information is collected in a varied spectrum of patients, and makes it likely that the study will yield data that may not have been captured in pre-marketing Phase III studies. Regulatory agencies may also require a company to conduct controlled clinical studies to investigate specific concerns and gather information about the drug under specific conditions of use when there is a suspected problem. However, post-approval studies are not a general regulatory requirement.

H. Conclusions

Given their complexity, drug discovery and development are long and costly processes and represent major challenges for the pharmaceutical industry. Numerous regulatory documents have been established to guide pharmaceutical companies through the specific procedures and to answer specific scientific questions regarding study design and conduct. Even though these documents certainly cover various important aspects of innovative drug development, some aspects are require further characterization; therefore, close interaction with regulatory and national health authorities is strongly recommended to increase the chance of a positive outcome.


  1. ICH Topic E 12 Principles for Clinical Evaluation of New Antihypertensive Drugs CPMP/ICH/541/00, June 2000
  2. ICH Topic E 14 The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs CHMP/ICH/2/04, November 2005
  3. Best Practice guidance for Pilot EMA HTA Parallel Scientific 4 Advice procedures (for consultation) EMA/109608/2014 Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/05/news_detail_002097
  4. ISO 9000 http://www.iso.org/iso/iso_catalogue/management_standards/
  5. ISO17005 http://www.iso.org/iso/catalogue_detail.htm?csnumber=29322
  6. Human Tissue Authority http://www.hta.gov.uk/
  7. WHO Quality practices in basic biomedical research (QPBR) 2010, 1-175
  8. ICH guideline M4S: The CTD-Safety ICH, August 2001
  9. ICH Safety guidelines http://www.ich.org/products/guidelines/safety/article/safety-guidelines.html
  10. ICH guideline M3(R2) on non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals EMA/CPMP/ICH/286/1995
  11. Guidance for Industry. CGMP for phase 1 investigational drugs July 2008
  12. Allen LA, Hernandez AF, O’Connor CM, Felker GM. End points for clinical trials in acute heart failure syndromes. J Am Coll Cardiol. 2009 Jun 16;53(24):2248-58
  13. European Medicines Agency: Scientific guidelines on the clinical safety and efficacy of medicines used in conditions affecting the heart and blood vessels. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_
  14. Blumer JL. Off-label uses of drugs in children. 1999;104:598-602
  15. European Medicines Agency. The European paediatric initiative: History of the Paediatric Regulation (EMEA/17967/04 Rev 1)
  16. Happu, K, Hirschfeld S, Zajicek A. Comparison of the US and EU paediatric initiatives. In Proceedings of WHO Expert Consultation on Essential Medicines for Children, Geneva, Switzerland, 9-13 July 2007
  17. Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EC) No 1902/2006
  18. ICH Topic E 11 Clinical Investigation of Medicinal Products in the Paediatric Population CPMP/ICH/2711/99
  19. European Commission Guideline on the format and content of applications for agreement or modification of a paediatric investigation plan and requests for waivers or deferrals and concerning the operation of the compliance check and on criteria for assessing significant studies (2008/C243/01) Available at: planhttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000266
  20. EMA/CHMP/QWP/805880/2012 Rev. 2 Guideline on pharmaceutical development of medicines for paediatric use.August 2013
  21. EMEA/CHMP/EWP/147013/2004 Corrigendum. Guideline on the role of pharmacokinetics in the development of medicinal products in the paediatric population June 2006
  22. De Cock RFW, Piana C, Krekels E-HJ, Danhof M, Allegaert K, Knibbe CAJ. The role of population PK-PD modeling in paediatric clinical research. Eur J Clin Pharmacol 2011; 67 (Suppl 1): S5-16
  23. Humbert M, Segal ES, Kiely DG, Carlsen J, Schwierin B, Hoeper MM. Results of European post-marketing surveillance of bosentan in pulmonary hypertension. Eur Respir J 2007; 30: 338–344


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