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considered sufﬁcient to support registration-enabling clinical trials and subsequent market-

ing authorization of anticancer biopharmaceuticals for the treatment of late-stage cancer.

Other considerations are highlighted in ICH S9 that inﬂuence the conduct and timing of

nonclinical studies to support an anticancer development program. For example, an em-

bryo-fetal development study in one species would typically be completed prior to

product registration but is not considered essential to allow clinical trials in patients with

late-stage cancer. This study may not be necessary if the target or drug class has been

well-characterized as causing developmental toxicity, or if the patient population is beyond

childbearing potential. Alternative approaches to conducting the DART study might be

possible and include literature assessment, understanding of placental transfer, and the po-

tential for direct or indirect effects of the biopharmaceutical on the developing fetus. If these

approaches are used, the developmental toxicity cause for concern would be reﬂected in the

product label and an EFD study would not be warranted. Any time an alternative approach

to conducting a toxicity study is being considered, consultation and agreement with the rele-

vant health authorities should be reached before proceeding with the approach. As for other

biopharmaceuticals, genotoxicity studies are generally not needed. In accordance with ICH

S9, carcinogenicity studies are not warranted to support marketing of drugs (small molecules

and biopharmaceuticals) intended to treat patients with advanced cancer.

Biopharmaceuticals planned for use in clinical combination studies (with another marketed

drug or biopharmaceutical/chemical entity in clinical development) should be well-

characterized individually in nonclinical toxicity studies. Potential therapeutic beneﬁtofa

combination needs to be justiﬁed by efﬁcacy assessment in pharmacology studies; however,

nonclinical toxicity studies to support clinical combination studies are not needed. When the

toxicity proﬁle of one of the drugs has not been well-characterized, then limited safety

endpoints from a supportive pharmacology study, such as mortality, clinical signs, and

body weight, may sufﬁce to show an increase in efﬁcacy without a substantial increase in

toxicity.

First-in-human (FIH) clinical trial

The nonclinical safety program consists of studies designed to provide sufﬁcient toxi-

cological data to support the safe administration of a new molecular entity to human be-

ings. Safety and tolera bility are the primary endpoints in the FIH or Phase 1 clinical trials,

which are typically conducted in healthy male volunteers where there is only risk and no

beneﬁt to the volunteers. Therefore, the type and design of toxicity studies is critical to

support the FIH trial. Although FIH trials conducted in patients alter the risk beneﬁt

slightly, the risk is still unknown. In addition to providing safety information, data

from nonclinical safety s tudies assist in the identiﬁcation of dose-limiting and target organ

toxicity and the evaluation for the potential of reversibility. Data from toxicity studies

should also provide an i ndication of risk for adverse clinical reactions for general and spe-

cial patient populations and understanding of doseeactivity relationships. The nonclinical

safety program using both in vitro and in vivo studies should build an experimental

database with which to allow safe progression into human trials from the FIH study to

registration.

3. Regulatory guidelines and their application in the nonclinical evaluation of biological medicines86

I. Development of biopharmaceuticals

Nonclinical safety program considerations

An understanding of the biology and mechanism of action of a biopharmaceutical is essen-

tial in the design of a nonclinical safety program and can be obtained from several sources

such as literature review, gene or protein expression patterns (target distribution), in vitro

binding and functional assays in animal and human cells, knockout animals, and nonclinical

and clinical data from similar products’ pharmacology. Because the toxicity of bio-

pharmaceuticals is primarily due to exaggerated pharmacology, an FIH nonclinical safety

assessment package can be more targeted than for small-molecule therapeutics, as shown

by Table 3.6. For a given target, the nonhuman primate may be the only relevant species

and since there are fewer animal models of disease or pharmacology models in nonhuman

primates, a rodent surrogate could be used at this early stage of development.

An FIH-enabling nonclinical safety package, in addition to in vitro and/or in vivo phar-

macology data, could include a GLP (Good Laboratory Practice) repeat-dose toxicity

stud(ies) in one or two biologically relevant species. The duration of the repeat-dose

studies is variable but would need to be at least as long as the duration of the proposed

clinical trial. Dose range ﬁnding studies should be conducted only if needed to aid in

dose level selection for the deﬁnitive GLP studies. Given both the species-speciﬁc

constraints of many biopharmaceutic als and th eir type of toxicity, separate safety pharma-

cology studies are not always required; safety pharmacology endpoints can be

incorporated into the repeat-dose toxicity study. For monoclonal antibodies (or related

antibody-like products containing complementarity determining regions (CDRs)), tissue

cross-reactivity studies using human tissues are a lso required (special consideration is

given for oncology biologics where the tissue cross-reactivity study may be waived if

TABLE 3.6 Toxicology studies required to support ﬁrst-in-human clinical trials.

Study

Small molecular weight

therapeutic Biotherapeutic

Standard FIH-enabling nonclinical safety assessment program

Repeat-dose toxicity study in rodent

and nonrodent

Yesdboth species Yesdonly relevant species

Genotoxicity studies Yesdin vitro and

micronucleus

Nodonly if contains chemical linker

SAFETY PHARMACOLOGY studies

Cardiovascular telemetry Yes Only for speciﬁc cause for concern

Rat respiratory Yes

hERG Yes Nodsize does matter

Tissue cross-reactivity No Yesdfor molecules containing a complementarity

determining region

Cytokine release No Yesdbut may not require actual in vitro assay

Speciﬁc endpoints (e.g., cardiovascular, CNS, respiratory) can be incorporated into general toxicity study.

First-in-human (FIH) clinical trial 87

I. Development of biopharmaceuticals

the target is well understood and there is no cause for concern- See Chapter 11 and (ICH,

2018). In addition, an assessment of the potential for cytokine release is generally expected

by Health Authorities.

Dealing with the datadNOAEL considerations

Since the primary purpose of a nonclinical toxicity study is to characterize the potential

toxicity proﬁle of a novel compound, the NOAEL is fundamental for both the identiﬁcation

of a safe starting dose as well as the stopping dose and/or criteria for the Phase 1 clinical trial.

The NOAEL is usually deﬁned as the highest tested dose or exposure at which there is no

signiﬁcant increase in the frequency or severity of harmful effects, alteration of morphology,

functional capacity, growth or lifespan between the exposed population and its appropriate

control. Therefore, with respect to biopharmaceuticals, the question is: When does exagger-

ated pharmacology become adverse? While the question seems simple enough to determine,

there are considerations speciﬁc for biopharmaceuticals that may complicate the answer.

ADAs, in addition to potentially producing changes in either pharmacological effects or

drug exposure, can also form antibody and antigen immune complexes which can produce

toxicity (e.g., ICD and glomerulonephritis). Although clearly adverse, the toxicity is not

caused directly by the biopharmaceutical and as immunogenicity in animals tends not to

be predictive for humans, the observed toxicity should not contribute to the NOAEL.

Many biopharmaceuticals have a long half-life so they may exhibit a complex temporal

relationship, and doseeresponse curves may be bell-shaped or ﬂat rather than linear. For

example, for antagonistic monoclonal antibodies, the low dose in a toxicity study is often

near the expected clinical efﬁcacious dose level which is typically near 90%e100% receptor

saturation and therefore all the dose levels will be near or at saturable receptor-binding; a

linear doseeresponse of an adverse ﬁnding would not be anticipated. In a study in which

there are ﬁndings of similar severity and incidence in the mid and high dose, there may be

a tendency to incorrectly suggest that the ﬁndings may not be treatment related because there

is no doseeresponse. Upregulation of soluble receptors by a biopharmaceutical which can

alter its clearance could also complicate the NOAEL determination.

Translation of nonclinical data to clinical trial dose selection

Selection of the starting dose for an FIH clinical trial is not speciﬁcally discussed in ICH

S6(R1), although the importance of doseeresponse assessment in early clinical trials is

addressed in ICH E4 (ICH, 1994) and the EMA guidance on ﬁrst-in-human clinical trials

(EMA, 2017). ICH M3(R2) recommends that in general the NOAEL in an appropriate animal

species is the most relevant for estimation of the ﬁrst dose in human but that other aspects

such as pharmacodynamics, molecular characteristics, and design of the clinical trials should

be considered. More detailed recommendations for estimation of st arting doses can be found

in various regional guidelines. The US Food and Drug Administration (FDA) published rec-

ommendations for a maximum recommended safe starting dose (MRSD) for FIH clinical tri-

als (July 2005), a guidance widely used by industry for small molecular weight therapeutics

(FDA, 2005). The guidance recommends a step-by-step approach in which the NOAEL is

3. Regulatory guidelines and their application in the nonclinical evaluation of biological medicines88

I. Development of biopharmaceuticals

determined in each of the toxicity studies and then is converted into a human equivalent dose

(HED) for each species, using body surface area to scale to human. The HED for the most sen-

sitive species is selected and then a tenfold safety factor is applied. Although the guidance

mentions that the pharmacologically active dose (PAD) should also be considered, it is a sec-

ondary focus of the guidance (FDA, 2005). However, for biopharmaceuticals, the MRSD as

determined from a NOAEL in animal studies may not be the most appropriate measure

and alternative dose-setting strategies should be considered (Muller et al., 2009). Other factors

such as the afﬁnity of the biopharmaceutical for the target and across species (i.e., potency),

understanding of the receptor occupancyeresponse relationships and the potential for “one

off” switch mechanisms (i.e., steep doseeresponse relationships) should be considered. The

importance of understanding the pharmacology (i.e., selection of a relevant species) and reli-

ance on toxicity and not biology was highlighted by the FIH clinical trial with an anti-CD28

monoclonal antibody (TeGenero TGN1412) that resulted in severe adverse effects in the

healthy volunteers (Suntharalingam et al., 2006). The Committee for Medicinal Products

for Human Use (CHMP) of the European Medicines Agency (EMA) published a risk manage-

ment strategy for FIH dose selection for “high” risk compounds (e.g., agonistic molecules,

those with steep doseeresponse curves, etc.). This guidance also deﬁned MABEL (minimal

anticipated biological effect level) (EMA, 2017). MABEL is similar to the PAD concept

suggested by the FDA’s FIH guidance mentioned above. Therefore, for biopharmaceuticals

selection of FIH dose should be based on expected pharmacology or biology as well as on

the NOAEL and exposure differences across species should also be taken into consideration.

Summary

The regulatory landscape has evolved signiﬁcantly for the nonclinical development of bio-

pharmaceuticals over the last couple of decades. This has resulted from an increased under-

standing of both the biology and potential toxicity of large protein molecules, including

recombinant proteins, monoclonal antibodies, their numerous derivatives, and conjugates,

and in particular the ﬁeld of immuno-oncology. During this evolution it has become clear

that the principles as originally set forth in the ICH S6 guideline, while still relevant, need

an update to offer recommendations on new alternative methods and to encourage scientif-

ically justiﬁed changes in study design and weight of evidence approaches that reduce the

use of animals. These foundational principles are based on using a case-by-case approach

for each biopharmaceutical, where the best science for understanding the biology and

potential toxicity of a molecule is used to design and implement the nonclinical program.

Because of the tremendous advances in biopharmaceutical drug development, the appetite

for reducing/eliminating the use of animals, (due to both the ethical concerns around using

and the scarcity of NHPs), there are topics in the now decade old ICH S6 (R1) guideline that

are in critical need of an update.

There will continue to be challenge s in the nonclinical development of biopharmaceuticals.

The goal, however, will remain the samedto use the best science and nonclinical study de-

signs available to aid in the understanding of any potential toxicity and to ensure patient

safety.

Summary 89

I. Development of biopharmaceuticals

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