preclinical development handbook || regulatory issues in preclinical safety studies (u.s. fda)

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27 REGULATORY ISSUES IN PRECLINICAL SAFETY STUDIES ( U . S . FDA )

Kenneth L. Hastings 1 and William J. Brock 2 1 sanofi -aventis, Bethesda, Maryland 2 Brock Scientifi c Consulting, LLC, Montgomery Village, Maryland

Preclinical Development Handbook: Toxicology, edited by Shayne Cox GadCopyright © 2008 John Wiley & Sons, Inc.

Contents

27.1 Introduction 27.2 Have Suffi cient Preclinical (Nonclinical) Toxicology Data Been Submitted? 27.3 Are the Doses Proposed for Clinical Trials Safe Based on Submitted Data? 27.4 Is the Length of Exposure Proposed for Clinical Trails Safe? 27.5 Additional Considerations 27.6 Conclusion References

27.1 INTRODUCTION

In drug development, it is important to know and understand the legislation and other “ high level ” documents (e.g., case law) establishing the regulatory authority of the FDA as well as the specifi c enabling documents that have been published (e.g., 21 CFR, ICH Guidances, FDA Guidances) and the supporting guidelines [1 – 10] . However, it is of practical importance to understand the scientifi c approach that ultimately drives decision making in the drug review divisions that constitute the real world of pharmaceutical development. The pivotal individual in applying phar-macology/toxicology principles and practice to drug development is the FDA reviewer. This individual has the task of interpreting data submitted by the sponsor and making the decisions critical to clinical drug development. Sometimes in trying

966 REGULATORY ISSUES IN PRECLINICAL SAFETY STUDIES (U.S. FDA)

to understand the drug review process, it is easy to lose sight of the “ big picture ” and become lost in the minutia. A very useful approach to understanding the review and decision - making process is knowing the fundamental questions needed to be answered by the somewhat bewildering list of published documents. The following list of questions will form the framework for discussing regulatory issues that, when dealt with incorrectly, can derail a drug development program:

• Have suffi cient preclinical (nonclinical) toxicology data been submitted? • Are the doses proposed for clinical trials safe based on submitted data? • Is the length of exposure proposed for clinical trials safe?

If sponsors keep these questions in mind when designing, conducting, and inter-preting preclinical drug safety studies, they will be thinking along the same lines as the pharmacology/toxicology reviewer. Each of these questions is discussed in turn.

27.2 HAVE SUFFICIENT PRECLINICAL (NONCLINICAL) TOXICOLOGY DATA BEEN SUBMITTED?

When attempting to answer this question, two documents are absolutely pivotal: ICH M3 and ICH S6. These documents provide key information on what studies are needed to enable clinical trials. ICH M3 also contains a chart that lists the studies needed to be completed prior to conduct of specifi c clinical studies (Table 27.1 ).

There are several issues that should be considered when interpreting what appears to be a rather simple paradigm. The fi rst is that the term “ repeat - dose toxic-ity studies ” is generally interpreted to mean daily oral doses. This is a relatively straightforward matter when considering a new molecular entity (NME) that will be administered in clinical trials by the oral route. However, when a drug will be administered by another route, interpretation becomes more complicated. There is no simple paradigm to which reference can be made, but rather a number of points to consider. The fi rst is whether the drug is an NME or not. If the drug has been previously developed for use by oral administration, it may be suffi cient to conduct what are generally referred to as “ bridging studies. ” For example, if a drug was originally developed for oral administration and suffi cient oral toxicology data are

TABLE 27.1 Duration of Toxicity Studies and Clinical Trials

Duration of Clinical Trials

Duration of Clinical Trials Toxicity Studies

Rodents Nonrodents

Single dose 2 weeks 2 weeks Up to 2 weeks 2 weeks 2 weeks Up to 1 month 1 month 1 month Up to 3 months 3 months 3 months Up to 6 months 6 months 6 months > 6 months 6 months Chronic: 9 months and longer

available, it may be possible to support clinical trials with repeat - dose toxicology studies by the new route of exposure (e.g., topical, inhalation) in one species (usually a nonrodent). Route - specifi c studies may need to be conducted (such as local irrita-tion), and toxicokinetic studies should be incorporated into the nonclinical develop-ment program to establish comparative local and systemic exposure. However, the important point is that a complete replication of toxicology studies conducted by the original route of exposure may not be necessary.

An interesting issue that often arises in the nonclinical toxicology evaluation of drugs is the role of acute dose studies. As a general rule, the package of enabling studies should contain acute dose toxicology studies in both rodents and nonrodents. Several points should be considered. The fi rst is the issue of what constitutes an acute dose study. Although occasionally a point of debate, it is generally accepted that an acute dose study is one in which the test article (drug) is administered as a single dose, or as more than one dose, in a single 24 hour period, followed by appro-priate clinical and anatomical evaluation. The studies should be conducted over a dose range suffi cient to demonstrate adverse effects and should be GLP compliant (21 CFR part 58). The second is that acute studies, as a general rule, are not usually suffi cient to support clinical trials. They are essentially “ discovery ” or hazard iden-tifi cation studies intended to determine the toxic potential of the test article. In fact, several studies may need to be conducted (usually in rodents) to determine the doses necessary to produce toxicity. There are examples of drugs for which acute toxicity studies may be adequate to support clinical trials (basically, agents that will be administered as a single dose in very circumscribed clinical settings, such as radioimaging agents or inhalation anesthetics), and there are specifi c situations recognized in regulatory guidances discussed later, but in general these are not suf-fi cient to initiate clinical trials. Finally, under most circumstances it is not necessary (in fact, it is discouraged) to determine lethal doses. Although acute dose toxicity studies may be useful in evaluating and managing overdose situations in clinical trials, and may eventually be used to write the overdose section of a product label, they are of limited practical use in the design and conduct of clinical trials. This leads to a consideration in designing toxicology studies to enable clinical trials: if appro-priate repeat - dose toxicology studies have been conducted, GLP - compliant acute dose studies may not be needed, or even appropriate, especially in nonhuman primates.

As mentioned earlier, there are specifi c guidance documents that allow for the use of acute dose toxicity studies to enable clinical trials. For the development of imaging agents, for example, it is acceptable to conduct acute dose toxicity studies with signifi cant caveats. First, the studies will need to be GLP compliant and con-ducted in both rodents and nonrodents, and animals should be monitored for the core battery of safety pharmacology parameters (cardiovascular, central nervous system, and pulmonary function) unless separate single - dose studies are conducted as described in ICH S7A. Second, complete clinical observations, clinical pathology (clinical chemistry and hematology), as well as necropsy and complete histological examinations must be conducted on day 2 (24 hours after test article administra-tion). Third, a recovery group must be included for every dose group with complete clinical and necropsy/histology determinations.

The second example is the screening IND . In most respects, screening IND studies should be conducted in a manner identical to those needed to support clini-

HAVE SUFFICIENT PRECLINICAL TOXICOLOGY DATA BEEN SUBMITTED? 967


cal trials with imaging agents. There are several additional considerations, however. The screening IND is designed to allow a sponsor to submit safety data on several related compounds. Although not explicitly defi ned, the term “ related compounds ” is assumed to mean both structurally and pharmacologically related. If the drugs are to be administered by the oral route in clinical trials, acute toxicity studies should be conducted by the intravenous route as well, with complete safety pharmacology, clinical pathology, and pathology determinations. Toxicokinetic determinations also should be included with particular emphasis on oral bioavailability. An ICH - compli-ant battery of genotoxicity studies should be conducted with each compound. The specifi c purpose of the screening IND paradigm is to enable single - dose clinical studies in healthy volunteers in order to select the most promising candidate com-pound. For further discussion of the different types of INDs and the regulatory process, the reader is referred to Mathieu [11] .

In 2006, the FDA published a comprehensive guidance entitled Exploratory IND Studies [8] . Although often referred to as a single approach, in fact the guidance describes several alternative approaches to fi rst - in - human (FIH) clinical trials, and the types of nonclinical studies needed to support these trials. The general approach is discussed later, but one concept in particular utilizes acute toxicity studies — the microdose clinical trial. Essentially, the design of acute dose toxicity studies builds on the screening IND approach described earlier with the notable exception that the safety of a proposed single - dose clinical trial can be determined using one mam-malian species. Selection of the species should be justifi ed using comparative in vitro pharmacokinetic and pharmacodynamic data (essentially, using animal and human tissues/cells), and the dose selected for use in clinical trials should be no more than 1/100 of the no - observed - adverse - effect level (NOAEL) in the test species, based on relative body surface area and not a mg/kg dose. Safety pharmacology and geno-toxicity studies are not needed. As a practical matter, the clinical trials are likely to be conducted using doses in the low microgram level (nanomole level for protein drugs), and the studies are designed primarily to determine (relative) oral bio-availability. Another possible clinical study endpoint is specifi c receptor binding (discovery pharmacodynamics).

In most instances, a battery of genotoxicity studies should be conducted and submitted for review prior to FIH clinical trials. These are hazard identifi cation tests and should include bacterial mutagenicity (Ames test) and at least one in vitro mammalian genotoxicity study (the mouse lymphoma assay and/or a chromosomal aberration assay). Prior to Phase II clinical trials, a complete battery of ICH S2B genotoxicity tests should be completed, which as a practical issue means an in vivo rodent micronucleus assay in addition to previously completed studies.

Other studies that are needed according to ICH M3 include determination of local tolerance (if the drug is to be administered by a nonoral route), a battery of ICH S7A safety pharmacology studies, and, prior to Phase III clinical trials, the ICH equivalent of Segment II reproductive toxicology studies. Other studies may also be needed, such as an intravenous toxicology study to enable clinical studies to determine absolute oral bioavailability. Studies to determine potential drug effects on cardiac function (e.g., hERG assay, in vivo cardiac function studies), as described in ICH S7B, should be submitted although these are not required. ICH S8 immu-notoxicity studies may be needed based on a weight - of - evidence analysis, primarily using results of repeat - dose toxicology studies. Some specifi c studies, such as assays

to determine the ability of topical drugs to cause allergic contact dermatitis, may be needed.

Chronic nonrodent toxicology studies are likely to be needed if the drug is to be used for more than 3 – 6 months. As discussed later, there are considerations in decid-ing the need for chronic toxicology studies, but these apply to a minority of drugs. There are “ regional differences ” in the defi nition of chronic use. In the United States, “ chronic toxicity studies ” are defi ned as 3 months of repeated exposure to the drug, or intermittent exposure equivalent to 3 months. ICH specifi es that a repeat - dose toxicology study in rodents of 6 months duration is adequate. For non-rodents, ICH defi nes the duration of a chronic repeat - dose toxicology study to be 9 months. However, for an NME that is the fi rst molecule in a class of compounds, it is likely that a 12 month repeat - dose study will be needed. Another situation in which a 12 month study may be expected is “ accelerated approval, ” where a fairly small clinical database is available for evaluation and, especially, where a surrogate marker is used as the effi cacy endpoint. On the other hand, a 6 month repeat - dose toxicology study might be deemed suffi cient if the drug belongs to a well - known class of drugs. Toxicities are sometimes observed that clearly limit the ability to conduct repeat - dose toxicity studies of greater than 6 months duration at clinically relevant doses. Lifetime rodent carcinogenicity bioassays (mouse and rat) will almost always be needed for drugs that will be used on a chronic basis. These studies are usually conducted late in the development of a drug and occasionally will be performed as part of postmarketing commitments. The FDA does not provide spe-cifi c guidance on the conduct of most types of nonclinical toxicology studies (with the notable exception of food additives), but in the case of carcinogenicity bioassays, concurrence on the study design should be requested by the sponsor via the protocol assessment review process.

Finally, biologic therapeutics (basically, protein drugs) represent a unique class of therapeutics and nonclinical studies needed to enable clinical trials are con-sidered in ICH S6. It is important to remember that ICH S6 and ICH M3 are com-plementary documents, and both apply to protein therapeutics. It is the exceptions to ICH M3 that should be noted when planning the development of protein drugs. For example, under most circumstances, rodents are not likely to be appropriate for evaluating the safety of protein drugs. In fact, it is the entire concept of “ appropriate animal model ” that leads to much of the misunderstanding in the design and inter-pretation of nonclinical toxicology studies with biologic products. Many of these drugs are immunogenic in animals other than nonhuman primates, and production of neutralizing antibodies in repeat - dose toxicology studies can render fi ndings irrelevant to human safety. If a protein drug is pharmacologically inactive in a species, it is highly likely that safety information will also be uninformative in this model. Unlike small molecular weight drugs, most toxicity observed with protein drugs are likely to be essentially exaggerated pharmacodynamics. There are certainly exceptions, but even under most circumstances these apparently “ off - target ” adverse effects will be observed only in species fairly closely related to humans.

There are many ways of dealing with the issue of species specifi city such as the use of homologous proteins that are pharmacologically active in a standard toxicol-ogy species (usually rodents) or the genetic manipulation of mice or rats such that they express the human receptor of interest (drug target) or lack the molecule

HAVE SUFFICIENT PRECLINICAL TOXICOLOGY DATA BEEN SUBMITTED? 969


(especially useful for evaluating protein antagonists or monoclonal antibodies to endogenous proteins). There are certain studies that are not needed to evaluate the safety of protein therapeutics. For example, genotoxicity studies and hERG assays are usually uninformative. In some cases, there may simply be no relevant animal model to evaluate the safety of a protein therapeutic, and consideration should be given to using in vitro data using human cells/tissues. This approach is discouraged by the FDA, but sometimes there will be no justifi able alternative. For example, consider a monoclonal antibody (mAb) directed at a human pathogenic virus. A standard method useful in evaluating potential safety concerns with the mAb is tissue cross - reactivity. Essentially, the mAb is tested with a bank of human (and animal) tissues to detect specifi c binding to expressed epitopes. If no binding is observed, it is highly likely that nonclincial toxicology studies will not be useful and that the safety of clinical studies cannot be evaluated using standard techniques. In the case of monoclonal antibodies to human epitopes, where no pharmacological effects are observed in nonhuman primates or other standard toxicology species, there are in vitro methods that utilize human cells and may be useful. For many (if not most) protein therapeutics, case - by - case study design should be the expected approach.

27.3 ARE THE DOSES PROPOSED FOR CLINICAL TRIALS SAFE BASED ON SUBMITTED DATA?

Extrapolation of doses from animals to humans is a critical issue in evaluating non-clinical toxicology studies. The key document to consult when converting animal doses to human equivalent doses is FDA Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers [6] . The general method presented in this guidance is based on comparative body surface areas and utilizes the standard conversion formula:

Human Equivalent Dose Animal Dose mg/kg

Animal Weight/Human W

=×

( )

( eeight) .0 33

This method is an inherently conservative approach and is intended to estimate systemic exposure to low molecular weight drugs. For example, if a dose of 30 mg/kg, when administered by the oral route to cynomolgus monkeys, produces an AUC of 50 μ g · h/mL, using this formula, the human equivalent dose (HED) would be 10 mg/kg, and if this dose is administered to an adult human volunteer, the measured AUC should also be ∼ 50 μ g · h/mL. There are of course many assumptions made in this method and include similar oral bioavailability and metabolism, and the method assumes that the drug has never been administered to humans, so no comparative pharmacokinetic data exist to test the calculation. In addition, the method is meant to apply to FIH doses in healthy volunteers. Therefore, an additional safety factor should be applied to the calculated HED. The default safety factor advocated in the guidance is 10, so the dose calculated in the example given above would be 1 mg/kg. The guidance allows for several considerations in calculating HED, such as steep-ness of the dose – response curve and nature of adverse effects observed (reversible or not, monitorable or not, etc.), and provides the sponsor the opportunity to present

data supporting an alternative method for estimating relative doses (such as body weight comparison). Although the default dose adjustment is referred to as a safety factor, it is in fact an uncertainty factor. Experience has demonstrated the method to be reliable for most classes of drugs. The exceptions include drugs delivered by routes of administration that do not result in appreciable systemic exposure, drugs that are extensively metabolized (where the object of the calculation is estimating comparative exposure to the parent drug), and protein drugs with a molecular weight ≥ 100,000 where distribution is primarily confi ned to the vascular compartment.

An important consideration in calculating a safe starting dose for clinical trials in healthy volunteers based on animal data is that a NOAEL has been determined. The NOAEL is the animal dose that will be used to calculate the FIH dose. In most cases, the FDA will take a conservative approach in identifying a NOAEL. Since most Phase I studies will be conducted in healthy volunteers, essentially no adverse effects should be anticipated when administering FIH doses. An issue frequently debated with sponsors is the simple question of whether a fi nding in an enabling repeat - dose toxicology study is in fact “ adverse. ” For example, should an increase in blood pressure of 10% compared to controls be considered adverse? Chances are the FDA would want to see a dose at which no increase in blood pressure was observed, but for certain drug classes this might be an unrealistic expectation. As discussed later, the pharmacologically active dose (PAD) is a consideration in cal-culating a safe starting dose. Depending on the intended use of the drug, blood pressure effects may be an important consideration, and if the HED at which the blood pressure effect is observed is higher than the anticipated PAD based on animal pharmacology studies, the PAD should be used to calculate the FIH dose. If the PAD is greater than the dose at which elevations in blood pressure are observed, it is likely that the FDA will consider the NOAEL to be the lower dose, and although pharmacokinetic data can be obtained in healthy volunteers, it is likely that phar-macologic activity studies will need to be conducted in patients rather than healthy volunteers.

The concept of NOAEL is important in one clinical trial design allowed under the Exploratory IND Studies guidance. The essential approach is that the sponsor would conduct a standard 2 - week repeat - dose toxicity study in animals (usually rodents), and a NOAEL would be determined. The sponsor would include a deter-mination of key pharmacokinetic (PK) parameters in this study, most importantly the AUC, C max , and t 1/2 . A 2 - week repeat - dose oral toxicity study would then be conducted in a second animal species (usually dogs), using only one dose level, cal-culated to be the NOAEL equivalent based on the fi rst species, and the same PK parameters determined. If the NOAEL in the fi rst species is equivalent to the second species based on relative body surface area, and if PK parameters at the NOAEL are equivalent, then the HED can be calculated and used to establish the FIH dose. If one species appears to be more sensitive based on observed effects (essentially, this would mean that adverse effects were observed in the second species at the NOAEL equivalent in the fi rst species), the sponsor would use the second species to determine the NOAEL in a 2 - week repeat - dose study. In either case, the FIH dose would be no greater than 1/50 of the NOAEL in the more sensi-tive species based on the relative body surface area calculation. The maximum clinical dose would be the lowest of the following:

ARE THE DOSES PROPOSED FOR CLINICAL TRIALS SAFE BASED 971


• One - fourth of the NOAEL determined in the fi rst species (usually rodents) • One - half of the AUC at the NOAEL in the fi rst species, or the AUC in the

second species (usually dogs) at the dose equivalent to the NOAEL in the fi rst species (whichever is lower)

• The PAD in humans, or • The dose at which an adverse clinical effect is observed

Although this seems a complicated scheme, it has the advantage of requiring less test article than would be needed for standard toxicity studies needed to enable FIH clinical trials, and the sponsor could conduct clinical trials of up to 7 days in duration in healthy volunteers to include the determination of PK parameters at steady - state blood levels. Other issues would also need to be addressed, such as genotoxicity and safety pharmacology, but the study design could support more rapid initiation of repeat - dose Phase I clinical trials.

One issue missing from this discussion has been studies to support traditional ascending - dose PK and maximum tolerated dose (MTD) Phase I clinical trials. These still have an important role in drug development. The body surface area dose calculation is relevant to dose setting in these studies. However, some classes of drugs continue to be evaluated in symptomatic patients rather than healthy volun-teers, and determination of safe starting dose may follow a different paradigm. For example, when developing cytotoxic chemotherapeutic agents for the treatment of cancer, Phase I studies are typically conducted in patients who are suffering from end - stage disease. In this situation, it has been judged acceptable to use a much more aggressive strategy in determining acceptable clinical doses. A traditional approach is to determine the lethal dose in 10% of animals (LD 10 ) — usually mice — and calculate the starting dose based on relative body surface area. Although rodents have been used to determine FIH doses, there is evidence that dogs may be more sensitive. However, there is an ongoing debate over whether increased sensitivity results in more effective dosing strategies. One issue to be considered in assessing the usefulness of a more sensitive species is that nonclinical toxicity studies in these animals may be limited with respect to discovering potential adverse effects. That is, it is at least worthy of consideration that use of a less sensitive species could allow for testing higher doses for longer durations, maximizing the possibility that impor-tant, clinically relevant toxicities may be revealed.

27.4 IS THE LENGTH OF EXPOSURE PROPOSED FOR CLINICAL TRIALS SAFE?

This is essentially a cumulative toxicity question. As presented earlier, ICH M3 explicitly states the length of nonclinical toxicity studies needed to support the safety of clinical trials. When designing a drug development program, it is important to consider the timing of nonclinical studies with respect to the duration of clinical trials. For example, the entire amount of time needed to conduct and evaluate fi nd-ings can be underestimated, which can result in “ delayed ” clinical development. As a general rule, the importance of this issue is often overestimated. That is, it is much more important to design and conduct enabling toxicology studies correctly — even

ADDITIONAL CONSIDERATIONS 973

if this seems to take more time than might be judged necessary — than to rush studies and commit errors that compromise the reliability of study results. Recruitment of subjects into clinical trials often takes much more time than anticipated; the clinical investigator usually underestimates this time and the numbers of subjects that can be recruited. Carefully conducted nonclinical studies can be extremely valuable, especially with respect to discovering toxicities that require repeated exposure — and often repeated insult — to demonstrate. Although in - life determinations can be useful, clinical chemistry and hematology signs are usually not “ leading indicators. ” When elevations in creatinine are observed, for example, it is likely that extensive kidney pathology has already been produced. Thus, reliance on in - life observations in nonclinical toxicology studies can be a risky clinical trial strategy.

One issue that has arisen repeatedly is the impact of positive fi ndings in geno-toxicity studies on the safety of clinical trials. When considering the signifi cance of genotoxicity in length of exposure, a weight - of - evidence approach should be taken [9] . Experience has indicated that often positive genotoxicity fi ndings can be related to product impurities, and it is important to make this determination as soon as possible. If positive genotoxicity fi ndings are due to drug contaminants, this may be a fairly easy situation to address. Another typical situation is a positive fi nding in an in vitro chromosomal aberration assay. This argues for inclusion of in vivo micro-nucleus assays as early as possible in nonclinical development. Many times the situ-ation that needs to be addressed is that the positive fi ndings in vitro were produced at high drug concentrations, bacterial mutagenicity assays were negative, and the mouse micronucleus assay is needed to clarify the nature of the hazard.

Carcinogenicity studies are rarely needed to enable clinical trials, but there are exceptions [4] . Clinical development of peroxisome proliferator - activated receptors (PPARs) represents a signifi cant departure from the norm. Current ad hoc policy in the FDA is to allow clinical trials with PPAR agonists for up to 6 months duration provided there are no other toxicities, especially genotoxicity or cardiotoxicity fi nd-ings, in nonclinical studies. However, in order to proceed with studies of longer duration, it may be necessary to complete carcinogenicity bioassays, thus signifi -cantly affecting clinical trials. Although this has not been adopted as formal policy, it remains the practice within the FDA.

27.5 ADDITIONAL CONSIDERATIONS

In addition to the three issues just discussed, there are other questions that the pharmacology/toxicology reviewer will likely want to answer. These may include:

• Are there patient or condition of use restrictions? • Do studies indicate the need for special monitoring or need for available

antidotes? • Are the demonstrated pharmacological effects relevant to the intended

indication? • Are adverse effects expected at effective doses? • What is known about related drugs? • What are the types and sites of toxic effects?


• Has the sponsor established a no observed adverse effect level (NOAEL)? • What is the apparent therapeutic index? • Are there irreversible or unmonitorable adverse effects? • Are there differences in metabolism of the drug, especially between animals

used in pivotal toxicology studies and humans?

These “ supplemental ” questions are no less important, but either apply to a subset of nonclinical studies or have been answered as part of the larger issues dealt with earlier. However, each deserves some comment.

Are There Patient or Condition of Use Restrictions? This question usually can be taken as referring to special populations. For example, if a drug is to be studied in clinical trials to prevent transmission of infections from mother to infant (perinatal transmission, e.g., HIV), the sponsor should conduct Segment I and III reproductive toxicology studies earlier than is usually expected [3] . Although these studies are conducted prior to submission of the NDA, these studies would need to be conducted prior to Phase II clinical trials (assuming pregnancy would not be an issue in Phase I studies). Although a relatively simple timing issue for most drugs, this could be a complicated issue with biologics. In fact, the entire issue of reproductive toxicology studies becomes complex when evaluating protein drugs. This is the single case where these types of studies may need to be conducted in nonhuman primates (NHPs). Although great effort is made to avoid these studies (e.g., development of transgenic rodent models expressing the target of interest for use in reproductive toxicology studies), often cynomolgus monkeys or other NHPs may be the only practical choice. A somewhat related topic is studies to enable pediatric drug trials. The FDA has published guidance on the types of juvenile animal studies useful in supporting the safety of clinical trials in infants, children, and adolescents, but the most important point is that these may not always be needed, and consultation with the FDA is encouraged. Length of exposure, age of the clinical trial subjects, and what is already known concerning the adverse effects of the drug are all issues that should be considered in deciding the need for juvenile animal studies [10] .

Another issue that should be dealt with under this question is the issue of pho-totoxicity and photoallergy [5] . The usefulness of nonclinical phototoxicity studies has been debated, and the FDA has published a guidance on this topic, but it is still somewhat unclear under what conditions nonclinical phototoxicity studies may be needed. Although generally considered in the development of topical drug products, this may also be an issue with drugs administered by other routes where systemic exposure results in signifi cant skin deposition. In fact, some of the most important phototoxic drugs (e.g., fl uoroquinolones) are given orally. The guidance relies on two parameters to determine the need for nonclinical phototoxicity studies: (1) sig-nifi cant molecular absorption in the UV - VIS spectrum and (2) concentration of the drug and/or metabolite(s) in the skin. Whether these are appropriate criteria can be questioned, however. Recently, the FDA has not requested photoallergy nonclinical studies since interpretation of the results continues to be debated.

Do Studies Indicate the Need for Special Monitoring or Need for Available Antidotes? Although often overlooked, risk management is an important issue to be dealt with in toxicology studies. Unfortunately, nonclinical toxicology studies


have not been utilized as well as possible in clinical trial design. There are examples of how these studies may be used. For example, if an association has been estab-lished in nonclinical studies between drug AUC and liver toxicity, this should be considered in the design and conduct of clinical trials. If a drug has been shown to cause anaphylactoid reactions, conditions associated with this adverse effect (such as rate of infusion for drugs given intravenously) should be used in the design of clinical trials, and appropriate antidotes (e.g., epinephrine) should be available during (and after) drug administration. There are a number of examples that could be cited, but the important point is to take into consideration toxicity fi ndings when considering the issue of risk management. The effort to discover and apply bio-markers of toxicity is a major driver in the FDA ’ s Critical Path Initiative.

Are the Demonstrated Pharmacological Effects Relevant to the Intended Indication? The answer to this question is often put in the “ nice to know ” category, but the importance of the issue should not be underestimated. An important con-sideration is that the review team at the FDA develops a perception of how effective a drug is likely to be and will sometimes act accordingly. Consider, for example, a drug intended to prevent organ transplant rejection. Especially in renal transplanta-tion, there are a number of effective drugs currently available. None are without adverse effect problems, but in general these have proved to be “ miracle ” drugs when used correctly. Thus, in developing a new drug for this indication, it is very important that proof - of - concept pharmacology studies provide compelling effi cacy data. One consideration is that usually a candidate drug for an organ transplant indication will likely be added to an ongoing cyclosporine - based immunosuppres-sive regimen. Nonclinical pharmacology studies should take this into consideration, and studies should be designed to demonstrate whether the candidate drug in any way interferes with the effi cacy of cyclosporine. The important consideration here is that sponsors ignore good proof - of - concept studies at their peril.

Are Adverse Effects Expected at Effective Doses? This is another risk management question and should be considered as early as possible in the development of a drug. There are many effective drugs on the market that produce headache, nausea, diar-rhea, and so on, in a signifi cant portion of the patient population. Many of these adverse effects will only be discovered in clinical trials, but signs of toxicity should be carefully considered in the design and conduct of these trials. Among the signs that can be misinterpreted are neurological effects in animals. Many animals can demonstrate signs of neurotoxicity, such as aberrant behavior in a functional obser-vation battery, that at fi rst seem not predictive of human effects. It is important to remember that animal behavior in response to adverse neurological effects may not, in fact often does not, have a direct correlation in humans. It is entirely conceivable that convulsions in animals may not be associated with similar effects in clinical trials but may signal that the drug does have the potential to produce seemingly unrelated effects in humans, such as depression or anxiety. Once again, sponsors ignore such fi ndings at their peril, especially where obvious adverse effects are observed in animals at target doses for development.

What Is Known About Related Drugs? As was pointed out earlier, the FDA has experience with a vast array of drugs. Many have failed in development due to


adverse effects, but fi ndings were never made public in publications. As part of the drug development program, it is incumbent on the sponsor to determine as thor-oughly as possible what is known in publicly available sources about possible drug class effects. It is also important that the sponsor address these potential class effects, often by design and conduct of specialized nonclinical studies or incorporation of additional observations in standard toxicology studies. Also, it is important to “ listen to the reviewer. ” All too often suggestions are made to a sponsor that particular attention be given to a specifi c issue and the advice is ignored. A wise sponsor listens to what is essentially free advice and considers it carefully.

What Are the Types and Sites of Toxic Effects? This is essentially a review issue, but as with so many questions in this list there are potentially important points to consider. One is related to the previous question. Simply put, if a drug belongs to a class with known toxicities, and these are not seen in submitted toxicology studies, several questions could be raised by the review team and include:

• Have they been conducted correctly? • Has a true MTD been achieved? • Were appropriate observations made and endpoints included? • Do TK data support that suffi cient systemic exposure was achieved?

As you can see, what is a seemingly straightforward issue that should be answered by the results of standard toxicology studies could become a very complicated problem. Another point to consider is whether the types of toxicities are “ accept-able ” given the intended indication. This can be a very complicated issue and should be addressed. For example, consider a drug that is intended to be administered by the topical route, and dermal toxicity studies have demonstrated relatively minor adverse effects at reasonable multiples of expected clinical doses. However, studies that maximize systemic exposure — that is, the studies were conducted by a paren-teral route of administration — demonstrate signifi cant toxicities associated with effective topical doses. These effects should not be ignored. It is frankly impossible to consider every scenario of use and discovery of a hazard should drive appropriate risk assessment studies. In this example, it may be adequate to demonstrate that, under conditions of use, signifi cant systemic exposure is so unlikely as to render the toxicity fi ndings irrelevant. A sponsor should never take such issues lightly — it is almost certain that the FDA will not.

Has the Sponsor Established a No Observed Adverse Effect Level ( NOAEL )? Although discussed extensively earlier, it is included here for emphasis. The sponsor must establish a NOAEL in most cases in order to enable FIH clinical trials. There are the usual exceptions (such as chemotherapeutic agents), but these are relatively obvious. A classic mistake made by sponsors is to conduct a nonclinical toxicology study intended to support the safety of a clinical trial in which no adverse effects are observed at one dose and serious toxicities, including death on study, are observed at the next highest dose. Based on the results of the study, the sponsor will claim to have established a NOAEL. Although technically correct, the sponsor has ignored the obvious implications of the study results. That is, either the range of doses was


too great to observe something equivalent to a lowest - observed - adverse - effect level (LOAEL) so that clinically appropriate toxicities were observed (i.e., adverse effects that may be monitored and when observed can be used to determine a reasonable stopping dose in a dose – escalation trial), or the dose – response curve is so steep with respect to serious toxicities that development of the drug is likely to be problematic. Issues such as this can seriously affect a drug development program and should not be taken lightly.

What Is the Apparent Therapeutic Index? This question is related to the previous one. All too frequently, sponsors will fail to consider results of nonclinical pharma-cology studies in the context of potential safety implications of fi ndings. A common mistake is to conduct a proof - of - concept pharmacology study in an animal model, demonstrate promising effects, and ignore serious toxicities. Enabling nonclinical toxicology studies are conducted, a NOAEL is established, Phase I studies are con-ducted, and what is discovered is that although a safe dose can be administered to humans, it is nowhere near the projected effi cacious dose based on pharmacology studies. This is actually a relatively easy issue to deal with as long as the sponsor conducts good studies and is willing to “ live with ” the results.

Are There Irreversible or Unmonitorable Adverse Effects? This issue can be a “ drug killer. ” There are a number of toxicities for which there are no adequate bio-markers of effect useful in clinical trials (especially prodromal markers). When observed, often the most important determination to make is the dose multiple at which the toxicity is observed. Although sometimes “ irreversible or unmonitorable adverse effects ” may be toxicologically insignifi cant, this is not the usual case. Thus, it is very important to establish the apparent therapeutic index. Other parameters that are important to establish include blood levels at which these adverse effects are observed (AUC, C max ); it is important to determine whether doses or systemic exposures needed to produce the adverse effects change with length of treatment (especially if the doses needed to produce the adverse effect are lower with longer exposures), and whether a clinically useful dose can be found where irreversible/unmonitorable adverse effects are not produced, with an appropriate safety margin. Although this is essentially the same as establishing an apparent therapeutic index, in fact, the toxicity used to determine this might occur at doses lower than those associated with the irreversible/unmonitorable effect and could provide an addi-tional margin of safety.

Are There Differences in Metabolism of the Drug, Especially Between Animals Used in Pivotal Toxicology Studies and Humans? This has emerged in recent years as a serious potential problem in drug development. Some authorities maintain that this is essentially an “ artifact ” of increased sensitivity of analytical methodology (tandem mass spectrometry, etc.). It is important that the sponsor determine as early as pos-sible in the drug development program whether there is/are relatively unique drug metabolite(s) produced by humans that have not been assessed for safety in non-clinical toxicology studies. The FDA has published guidance on this topic [6] . Essen-tially, the guidance recommends that the sponsor determine, possibly using in vitro methods such as isolated human hepatocytes/liver slices/microsomes, whether unique (or disproportionately abundant) metabolites exist compared to species


used in toxicology studies, and be prepared to deal with the issue proactively. This could mean that the sponsor might need to conduct essentially “ bridging toxicology ” studies with synthesized metabolite. There are other considerations, however, such as relative amount of metabolite. The FDA guidance has set (rather arbitrarily) 10% of administered dose or systemic exposure (both relative to parent drug) as the “ concern level ” for a unique or “ overabundant ” metabolite. It is recommended that the sponsor consult the FDA when such situations arise during drug development.

27.6 CONCLUSION

A wise man once said that every new drug requires a new development program. This is very close to the truth. Drug development should be approached as what it, in fact, is: a scientifi c experiment. There are few if any “ givens ” in drug development, which is why it is a risky proposition. Seek advice whenever needed, and consider it carefully when offered.

REFERENCES

1. FDA Guidance website: http://www.fda.gov/cder/guidance/index.htm . 2. ICH Guidance website: http://www.ich.org/cache/compo/276 - 254 - 1.html . 3. Integration of Study Results to Assess Concerns about Human Reproductive and Devel-

opmental Toxicities . Washington, DC: FDA; 2001 . 4. Carcinogenicity Study Protocol Submissions . Washington, DC: FDA; 2002 . 5. Photosafety Testing . Washington, DC: FDA; 2003 . 6. Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical

Trials for Therapeutics in Adult Healthy Volunteers . Washington, DC: FDA; 2005 . 7. Safety Testing of Drug Metabolites . Washington, DC: FDA; 2005 . 8. Exploratory IND Studies . Washington, DC: FDA; 2006 . 9. Recommended Approaches to Integration of Genetic Toxicology Study Results . Washing-

ton, DC: FDA; 2006 . 10. Nonclinical Safety Evaluation of Pediatric Drug Products . Washington, DC: FDA; 2006 . 11. Mathieu M. New Drug Development: A Regulatory Overview , 7th ed. Waltham, MA :

Parexel ; 2005 .

preclinical development handbook || regulatory issues in preclinical safety studies (u.s. fda)

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