The EMEA Guideline on First-in-Human Clinical Trials and Its Impact on Pharmaceutical Development

Introduction

On March 13, 2006, TGN1412, a monoclonal antibody, was administered to humans for the first time. Severe, life-threatening toxicities ensued. The science behind these adverse events and the immediate responses to this event have been described in another article (Horvath and Milton 2009). The TeGenero incident was a wake-up call to the pharmaceutical industry, the clinical trials community, and the regulatory agencies. The incident was investigated thoroughly by several different groups, including the Expert Group on Phase One Clinical Trials (chaired by Professor Gordon Duff), the Royal Statistical Society, and the Early Stage Clinical Trial Task-force. Each of these groups issued reports that summarized the causes of the adverse events and proposed ways that such adverse events could be avoided in future first-in-human (FIH) studies (Expert Group on Phase One Clinical Trials 2006; Medicines and Healthcare Products Regulatory Agency [MHRA] 2006; Early Stage Clinical Trial Taskforce 2007; Senn et al. 2007; Royal Statistical Society 2007). At the same time as these reports were being created, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA) was working on creating a guideline on strategies to identify and mitigate risks for FIH clinical trials with investigational medicinal products.

The Creation of the EMEA Guideline

In January 2007, there was an announcement that a guideline on “Requirements for First-in-Man Clinical Trials for Potential High-Risk Medicinal Products” would be created, and approximately six months later, the guideline was finalized (EMEA 2007c, 2007d). The draft guideline was released for consultation on March 22, 2007, with the end of the consultation period (the deadline for comments) being May 23, 2007. Comments on the draft guideline were received from over fifty-eight different organizations, companies, and institutes. The summarized comments on the draft guideline and the CHMP’s response to these comments are all available on the EMEA’s Web site, as is the original draft guideline (EMEA 2008). This transparency is in contrast to the FDA’s practice of removing draft versions from the Web page after finalization. The FDA also does not provide the responses to the comments that the interested parties have submitted to the docket. Obtaining the submitted comments from the FDA Web site is feasible but not easily achieved. The EMEA then hosted a workshop on the draft version of the guideline on June 12, 2007 (EMEA 2007a). The workshop covered background information on the TGN1412 case, the details of the draft guideline, and the comments that were provided on the draft guideline. Breakout sessions that covered the major areas of the draft guideline were also held. The guideline was adopted by the CHMP on July 19, 2007, and came into effect on September 1, 2007 (EMEA 2007c).

As an aside, it should be noted that within two weeks of the TeGenero incident, the CHMP issued a concept paper on the “Development of a CHMP Guideline on the Non-Clinical Requirements to Support Early Phase I Clinical Trials with Pharmaceutical Compounds” (EMEA 2006). However, the timing of the release of this concept paper was purely coincidental since it had been agreed on with the Safety Working Party (SWP) in February 2006. In addition, the thrust of the concept paper was to expedite the initiation of clinical trials in a manner similar to the FDA’s Guidance on Exploratory INDs (FDA 2006). The current (2008–2009) work plan for the SWP indicates that a draft guideline will be released for review in 4Q 2008 (EMEA 2007e). The national health authority in Belgium, the Belgian Federal Agency for Medicines and Health Products (2006), has produced a document, “Guidance to the Conduct of Exploratory Trials in Belgium,” that is a working document concerning the conduct of clinical exploratory trials in Belgium. This document was produced under political pressure and is not yet finalized. Despite these limitations, this document complements the EMEA guideline since it provides additional detail in certain areas.

The finalized EMEA guideline differed from the draft guideline in several ways, including the title. The title of the finalized guideline is “Guideline on Strategies to Identify and Mitigate Risks for First-in-Human Clinical Trials with Investigational Medicinal Products” (EMEA 2007c), whereas the title of the draft guideline was “Guideline on Requirements for First-in-Man Clinical Trials for Potential High-Risk Medicinal Products” (EMEA 2007b). The subtle change in title highlights a change in the intent of the guideline from “potential high-risk medicinal” products to all investigational medicinal products (IMPs). Implicit in this is the belief that any IMP is potentially high risk unless data exist to the contrary. In addition, the scope of the draft guidance was expanded from a focus on biologics to include both biologics and new chemical entities (NCEs). These changes arose based on the written comments that were provided by interested stakeholders, as well as discussions at a workshop that was held on the draft guidance. Some of the comments that were provided by interested parties who were primarily focused on the development of biologics seem to imply that biologics were being unduly singled out and that, if such a guideline were to be implemented, it should apply to both biologics and NCEs. The decision to expand the scope of the guideline to apply to both biologics and NCEs is a prudent decision because it places the focus on the pharmacology of the target and the properties of a product rather than the categorization of a given clinical candidate. Despite the fact that the guideline applies to both biologics and NCEs, the heritage of the guideline is quite clear, and the guideline reads very much like a biologics guideline into which some mention of NCEs has been inserted.

The Content of The EMEA Guideline

The guideline is wide-ranging in scope and is intended to assist sponsors in the transition from nonclinical to early clinical development. It identifies factors influencing risk for new investigational medicinal products and considers quality aspects, nonclinical and clinical testing strategies, and designs for FIH clinical trials. Strategies for mitigating and managing risk are given, including the calculation of the initial dose to be used in humans, the subsequent dose escalation, and the conduct of the clinical trial.

The guideline is not a stand-alone document and should be read in conjunction with several nonclinical and clinical EU guidelines. These guidelines include the following:

It should be noted that an expert working group has been established to write an addendum to the ICH S6 guidance (ICH 2008a). A clarification (and sometimes amplification) of this guidance is needed as substantial experience and new information has been gained since 1997. Disharmony across regulatory regions was identified to be a result of differences in implementation and interpretation of the S6 guidance and in part because of regional specific “Points to Consider” documents. The addendum will address species selection, study design, reproductive/developmental toxicity, carcinogenicity, and immunogenicity, although at this time, it is unclear as to the exact details and impact of the addendum. It is hoped that the addendum will reach Step 2 (i.e., be available for review) in November 2009 and Step 4 (i.e., adoption) in June 2010.

The focus of risk identification and risk mitigation before performing a FIH study is a somewhat new approach. Previously, the approach had been primarily focused on hazard identification (a description of the danger; i.e., what are the target organ[s] and adverse effects caused by the agent) with a lesser emphasis on risk identification (the likelihood of a toxic effect at expected exposure levels and conditions) and risk mitigation. The distinction between hazard identification and risk identification may appear to be a subtle one, but the difference is important. A compound that may have a high or hazardous profile may pose no risk to humans if exposure levels are low and the toxic potency is low. In addition, the mention of the pediatric population is an interesting one because it is very rare (if it has ever occurred before) that the first time that a novel IMP was administered to a human would be to a child rather than to an adult. One can only speculate as to why this population was specifically mentioned unless the intent was for the guideline to be used for first-time administration to a new subject population.

Various risk factors that should be taken into account are described in the guideline at both a high level and at a very detailed level. At the high level, the guideline states, “Predicting the potential severe adverse reactions for the first-in-human use of an investigational medicinal product involves the identification of the factors of risk. Concerns may be derived from particular knowledge or lack thereof regarding the mode of action, the nature of the target, and/or the relevance of animal models.” This statement makes the point that absence of evidence is not the same as evidence of absence and starts to lay the groundwork for the conclusion that new products should be regarded as having high risk unless data exist to the contrary.

The guideline then describes in great depth the criteria that should be discussed in the Clinical Trial Authorization (CTA) application for an FIH study. The list is lengthy and is not intended to be a checklist, since the guideline also notes that the criteria should be taken into account on a case-by-case basis. However, the mere existence of such a list will inevitably mean that it will be viewed as a checklist. Similarly, the guideline describes in great length the information that should be available related to the following:

It should be noted that the risk assessment will be performed on a “case-by-case” basis and that a “weight-of-evidence” approach will be used. This confirms the approach advocated by ICH S6 and suggests that such an approach is just as valid for NCEs as it is for biologics. In the opinion of the authors, this is an important and appropriate principle, especially with the realization that some NCEs (e.g., PEGylated small molecule compounds) and some synthetic compounds (e.g., peptides and oligonucleotide compounds) may have properties similar to biologics.

The guideline notes that novel mechanisms of action (MOA) do not necessarily add to the risk, per se, but consideration should be given to the novelty and extent of knowledge of the supposed mode of action. This statement alludes to the fact that we may not know the primary MOA at the time of the FIH study, as was the case with pregabalin (Lyrica^®, Pfizer; Silverman 2008). At the time of the FIH study for this compound, it was believed that the MOA was activation of L-glutamic acid decarboxylase (GAD). Subsequently, it was discovered that this was not the MOA and that pregabalin’s true MOA was binding to the α₂δ subunit of voltage-gated calcium channels. According to the guideline, the type of knowledge that may be required includes the nature and intensity (extent, amplification, duration, reversibility) of the effect on the specific target and nontargets and subsequent mechanisms, if applicable. This simple statement contains two important points, namely, the importance of nontarget-mediated (i.e., off-target) effects and the importance of the downstream effects of the interaction of the product with its target. It is presumed that nontarget in this context is synonymous with “nonintended target.” Additional information related to the nature of the dose response (steepness, shape, linearity, presence of a maximum effect) is also recommended. The guideline identifies certain modes of action that might require special attention. These include targets that have pleiotropic effects or are ubiquitously expressed (e.g., as often occur in the immune system) and those that have a biological cascade or cytokine release, including those leading to an amplification of an effect that might not be sufficiently controlled by a physiologic feedback mechanism (e.g., in the immune system or blood coagulation system). Monoclonal antibodies against the T cell targets CD3 or CD28 are given as examples of products that have this latter type of MOA.

The analysis of the risks associated with a given MOA not only should be based on data generated for a particular target but should also take into account data generated from the previous exposure of humans to compounds that have related modes of action and evidence from genetically modified animal models (transgenic, knock-in, or knock-out). Interestingly, the guideline does not describe the use of data from humans with genetic polymorphisms in the intended target or related to the intended MOA. Such data would be far more informative than the corresponding animal data. For example, the primary pharmacologic effects of administration of an anti-CD18 monoclonal antibody (i.e., leukocytosis and increased susceptibility to infection) are predicted by the phenotype of individuals with leukocyte adhesion deficiency (LAD), related to one of several functional defects in this selectin (Sharar et al. 1991; Etzioni 2007).

In addition to an understanding of the intended MOA, it is expected that the sponsor will provide a detailed description of the nature of the target. This information may include information on the structure, tissue distribution, cell specificity, disease specificity, regulation, polymorphisms, level of expression, and biological function of the human target, including “downstream” effects, and how it might vary between individuals in different populations of healthy subjects and patients.

Because the selection of the starting dose for an FIH study will be based on animal data from either toxicology or pharmacology studies, it is not surprising that the guideline also recommends that the sponsor should address the relevance of the animal models (species). This topic is addressed in two separate sections of the guideline. The guideline emphasizes that a weight-of-evidence approach should be used for determining the relevance of the animal models and that if the animal models are of questionable relevance for the investigation of the toxicological and/or pharmacological properties of the IMP, then this should be considered as adding to the risk. That is, the results of preclinical testing are relevant only to the extent that the target biology and compound pharmacology are comparable to humans. For this reason, it is incumbent on the sponsor to demonstrate convincingly the relevance of the chosen animal species.

The EMEA guideline describes the assessment of the relevance of the animal models as taking into account many factors, including the target, its structural homology, distribution, signal transduction pathways, the nature of the pharmacological effects, and metabolism and other pharmacokinetic aspects. The guideline places a clear emphasis on the need to ensure that the species used in the toxicology studies are pharmacologically relevant, with lesser emphasis on similarity of the metabolism of the clinical candidate in animals and humans (as has typically been the case for NCEs). The use of nonrelevant species in toxicology studies is strongly discouraged. Although pharmacological relevance is often part of the justification of the selection of the species to be used for the safety evaluation of biologics, it is rarely the case for NCEs, where the selection of the species used for the toxicology studies traditionally uses exposure and/or metabolism data. In reality, such data are most often used to justify the selection of the dog (for NCEs) and monkeys (for biologics) as the nonrodent species to be used in the toxicology studies. The rat is almost universally used as the rodent species in safety assessment studies for NCEs (Baldrick 2008), with very little justification for the selection of this species other than historical precedent.

The description of the elements that are important in the selection of the relevant species clearly shows that this guidance was originally written with biologics in mind and was not intended to be applied to NCEs. Yet the preclinical studies for NCEs traditionally emphasize comparative in vitro metabolism and biodistribution studies as part of the species selection criteria. Little, if any, mention is given in the guideline to the distribution of the product within the body and the metabolism of the product by the body. For a biologic, it is usually assumed that the compound will distribute poorly to tissues and be essentially restricted to the blood due its size. By contrast, NCEs will more readily distribute throughout the body due to their relatively small size. The concentrations of NCEs in tissues will also be affected by the metabolism and/or active transport of these agents. Therefore, an assessment of the relevance of a given species should take into account not only the distribution of the target in different tissues but also the distribution of the compound to those tissues in which the target is expressed. It should be noted that little data exist related to the relationship between the distribution of an NCE in animals and in humans.

With so much weight being given to the importance of pharmacological relevance in the selection of the species to be used in the toxicology studies, it is possible that clinical trial participants could encounter greater risk if toxicologic mechanisms are not fully evaluated. The guideline clearly gives the impression that the risk will most likely arise from biologic mechanisms (i.e., the intended pharmacological mechanism) rather than from chemical mechanisms. This is not surprising given the genesis of this guideline (i.e., as a guideline focused on biologics and the traditional focus on exaggerated pharmacology as the mechanism of toxicity for most biologics). It is assumed (as stated in ICH S6) that metabolism of biologics will yield small peptides and individual amino acids and that classical biotransformation studies as performed for NCEs are not needed (ICH 1996). It is also commonly assumed that any metabolites that are generated do not have a pharmacological and/or toxicological profile that is different than that of the parent molecule. However, it should be noted that such assumptions may not be valid in all cases (e.g., for oligonucleotide-based products, fusion proteins, and immunoconjugates). In addition, most biologics are very selective and have limited cross-reactivity with targets other than the intended target. The opposite is true for NCEs, where metabolism can result in molecules with altered pharmacological and toxicological properties and where both the parent and the metabolites may cross-react with targets other than the intended pharmacological target. Consequently, this leads to the possibility that unless one is careful, a focus on MOA-based toxicity may underestimate the human toxicity risk for NCEs, especially if the toxicity is caused by a metabolite. Although the FDA (2008) has issued a guidance on the safety testing of drug metabolites, this guidance was not intended to address FIH studies. Clearly, the challenge in the selection of the relevant species serves to emphasize the need for an extensive, weight-of-evidence approach in which both pharmacological and metabolic relevance are considered.

The EMEA guideline also addresses several CMC aspects. Briefly, the guideline notes that the sponsor should determine the strength and potency of the product, that the material used in nonclinical studies should be representative of the material to be used in the FIH study, and that the sponsor should demonstrate that very small doses can be accurately administered if the doses to be used in the FIH study are very low.

The Impact of The TeGenero Incident on Pharmaceutical Development

Since the TeGenero incident took place, those of us engaged in preclinical development have been swamped with suggestions for reducing the risks for the subjects who participate in FIH studies from a variety of sources (expert reports, editorials, guidelines, etc.), and it can be difficult to reconcile them all. These suggestions affect the disciplines of pharmacology, pharmacokinetics and pharmacodynamics, and toxicology. However, once we have understood what is now required of us, we are left to determine who should implement the recommendations in the guideline. There are many potential implications of the EMEA guideline and many points to consider. Some of these points to consider and potential impacts are summarized in Table 1.

It is clear that FIH clinical trials will be conducted in an even more cautious manner and that they will take longer to conduct and be costlier. It may be reasonable to speculate that sponsors would move FIH clinical trials away from the EU. However, it is also reasonable to anticipate that the FDA would default to the approaches described in the EMEA guideline, even though they may not issue their own guidance on this topic. Historically, many sponsors developing biologics have conducted their FIH trials in the EU, particularly prior to the replacement of the Clinical Trial Exemption (CTX) with the Clinical Trial Application (CTA). It will be interesting to see how the regulatory environment for FIH studies continues to evolve. For example, will the expectation be that the same cautious approach should be taken each time that the product is studied in a new population for the first time (e.g., patient vs. NHV; children vs. adults; single dose vs. multiple dose; drug-drug interaction studies)? Will the role and/or rigor of the pharmacology or toxicology review be increased? For example, the EMEA do not presently require the individual study reports for review prior to approving the FIH protocol but may decide that going forward, these documents should be made available to them as part of their review, as is the case in the United States. Despite the increased awareness of the risks inherent in FIH studies with high-risk medicinal products, there does not seem to have been much, if any, effect on the conduct of FIH clinical trials in the United Kingdom. At the 2008 annual meeting of the Drug Information Assocation, sponsors were encouraged to seek advice from the MHRA before submitting their IMPDs. The MHRA have a flexible approach and prefer to review medicinal products on a case-by-case basis rather than a “by-the-book” basis. The MHRA are more frequently advising sponsors that their products are not high-risk medicinal products than they are advising them that their products are high-risk medicinal products. In the period 2007 to May 2008, 267 Phase 1 clinical trials were conducted in the United Kingdom. Of these, the MHRA identified five products (< 2%) as being high risk, and only one of these products was discussed with an external advisory group. In addition, there does not appear to be an impact on the review cycle for the IMPD. In April and May 2008, 46 Phase I clinical trial applications were reviewed with an average review time of 12.5 days (Jones 2008).

Undoubtedly, the TeGenero incident has brought pharmaceutical testing into the spotlight, particularly for trials using human volunteers. The period from the time of the TeGenero incident until early July 2008 was very quiet in terms of adverse events in Phase I clinical trials with NCEs or biologics. In early July, a participant in a Phase 1 study to evaluate the bioavailability of RhuDex^® in a new formulation suffered a heart problem several days after administration of the drug and subsequently died (MediGene 2008). RhuDex^® is an orally administered disease-modifying antirheumatic drug (DMARD) that is designed to inhibit T cell activation by blocking the CD80 receptor, which will lead to a decrease in inflammatory cytokines. RhuDex^® has been administered to approximately eighty individuals, and positive safety data have been announced in a Phase IIa trial in patients with rheumatoid arthritis. At this point in time (approximately 2 weeks after the tragic death of the clinical trial participant), it is uncertain as to the role of the drug in this adverse event, but the reporting of the event by the press in the United Kingdom shows a keen interest in the protection of the safety of volunteers in clinical trials (Sweeney 2008).

Despite all of these concerns and the changes in the regulatory environment, not much will change in how we prepare for FIH studies. We will be essentially conducting the same work that we have previously, although we will be looking at the data and literature in a far more critical manner. There will be an increased need for integration of data and interpretations across disciplines, rather than the current, somewhat line-function-based approach. In reality, the distinction of roles based on line functions is outdated, particularly for companies that are developing biologics where the toxicity is due to exaggerated pharmacology. In this case, it is difficult, if not impossible, to tell where pharmacology ends and toxicology begins. For this reason, it is essential that toxicologists developing biologics become better acquainted with pharmacology (and immunology). The pharmacologist and toxicologist should work very closely together or even be one and the same person. This will open up opportunities for the toxicologist to act as a leader on cross-functional project teams, at least as it pertains to the identification and mitigation of risks in the FIH clinical trial. The toxicologist may be able work in close collaboration with the clinician to use preclinical data to forecast what pharmacodynamic activity will occur at each dose level in the FIH study rather than the standard current practice of advising what dose levels are not acceptable for the FIH dose. This enhanced requirement for a pharmacology-based approach to nonclinical safety assessment would logically extend to the pharmacology/toxicology reviewers in regulatory agencies, despite recent trends in the opposite direction (e.g., CDER assuming responsibility for CBER projects at the FDA).

Conclusions

At first blush, the TeGenero incident appears to have had rapid and far-reaching effects on the preclinical development programs to support FIH clinical trials. The most tangible of these is creation of the EMEA guideline for identification and mitigation of risk in FIH studies. This guideline builds on the foundation of ICH S6, in which a case-by-case, science-driven approach to safety testing is described, and the FDA guidance for estimating FIH starting doses, with additional emphasis on understanding and projecting the likely effects of the first pharmacologically active dose administered to humans. For perhaps the first time, this approach is now implicitly condoned for NCEs as well as for biologics and emphasizes a thorough understanding of the pharmacology in addition to the toxicology. We may never be able to tell whether the guideline has indeed improved the safety of the clinical trial participants due to the extreme rarity of the types of events such as the TeGenero incident. The EMEA guideline will, however, undoubtedly reduce the risk for participants in clinical trails, although there will be consequences of this added caution. It is likely that there will be an increase in the cost and time required to develop a product and a decrease in productivity of development organizations, particularly prior to Phase II testing. In addition, the pharmaceutical industry may be less willing to develop products for novel and unvalidated targets, especially for the treatment of small patient populations. It is probable that if the EMEA guideline had been in place at the time of the TeGenero clinical trial, the events that unfolded after the administration of TGN1412 to the first dose cohort would not have occurred. However, it is quite possible that the guidance may have simply delayed the inevitable tragic consequences of the administration of TGN1412 to healthy volunteers until a higher dose level.

Regardless, the EMEA guideline is here to stay, and it is up to us to determine how to safely and effectively develop products in this new regulatory environment. Whatever we do, we should ensure the safety of the clinical trial participants and work diligently to ensure that the events of March 2006 do not occur again.