Facts Flashcards
Stages of preclinical development
• M0: initial definition of a program;
• M1: selection of a drug candidate and of an indication;
• M2: first administration to humans;
• M3: first clinical efficacy data in humans (proof-of-concept
Washout period in cross over design
‘Sufficient washout periods ’ are often recommended to reduce or eliminate carryover effects. In practice it can be difficult to define sufficient. For a pharmacologic intervention, knowledge of kinetics can be valuable in the planning stages. For example, after seven half-lives less than 1% of the agent remains; at this time point meaningful pharmacologic carryover is removed for many drugs. If the effect of the agent is reasonably rapid and the outcome is closely related to physiological concentration then this might be all of the information that is needed. Other situations might be more complicated if pharmacodynamic effects persist beyond the physical elimination of the drug.
Types of two period designs to show disease modifying treatment effect
Withdrawal design
Delayed start design
Combination of withdrawal and delayed start design
Definition of term parameter
The term parameter refers to a numerical characteristic of a statistical population. In contrast, the term statistic refers to a value calculated in a sample. We are particularly interested in a type of statistic known as an estimate. A statistical estimate is a direct reflection of an underlying population parameter.
What is the statistical population
The statistical population is the entire collection of values (the “universe” of values) about which we want to draw conclusions.
Definition of power
Confidence is the complement of α, and power is the complement of β. Confidence ≡ 1 − α Power ≡ 1 − β
Selection of endpoints in middle stage development depends on what
Endpoint selection in early efficacy trials depends on the nature of the drug effect expected, previous experience with measurement scales used in the disease state, and the kind of decision problem faced by the study team. h e specii c endpoints selected should balance the need to measure the ef ect of the drug on the disease state, provide some initial reassurance that the drug ef ect is clinically meaningful, and have adequate operating characteristics for studies that typically are of somewhat smaller sample size.
Why is adequate washout period important for crossover design
Unwanted bias in the estimated treatment effect attributable to a carryover effect has already been described (‘Unequal carryover’).
The carryover effect can be found through data analysis, and when this effect is significant, it is difficult to interpret the treatment effect. Therefore, a protocol such as the above-mentioned washout period setting is an appropriate method to eliminate this effect.
Purpose of treatment withdrawal for checking disease modifying effects
h e purpose of the withdrawal maneuver is to determine whether any portion of the treatment ef ect that is evident at the end of Period 1 persists at er withdrawal of treatment, i.e., to distinguish between the short-term symptomatic ef ect and the disease-modifying ef ect.
What does the delayed start design share with the withdrawal design?
The delayed start design shares with the withdrawal design the potential problem that there is no blinding with respect to the treatment received during Period 2.
What are some limitations of two period designs
h ere are several limitations that accompany the use of two-period designs to determine whether or not an intervention has disease-modifying ef ects. Many of these have already been discussed, including the assumptions that: 1) Period 1 is long enough for a detectable disease-modifying ef ect to become apparent; 2) the disease-modifying ef ect acquired over the duration of Period 1 remains with the participant at least through the end of Period 2, but presumably longer; 3) Period 2 is long enough for the symptomatic ef ect from Period 1 to completely disappear by the end of Period 2; 4) withdrawal of active treatment does not modify (e.g., hasten) the disease process in some way (withdrawal design); and 5) the total (symptomatic + disease-modifying) ef ect of treatment received in Period 2 is independent of whether or not the participant received treatment during Period 1 (delayed start design), implying that Period 2 is long enough for the symptomatic ef ect of the treatment to become fully apparent.
Enrichment trial design
Clinical trials using enrichment designs involve at least two periods ( Figure 12.1 ). In the i rst period, the enrichment period, subjects are screened for their responsiveness according to predetermined criteria (e.g. a 30% reduction in baseline pain intensity). h ese criteria vary depending on the type of study being performed. Researchers ot en use the putative response to the treatment to be studied in the subsequent phase of the trial as a direct screening tool during the enrichment period. However, some researchers use other screening criteria such as biomarkers that may indicate potential response to the intervention. h is may be particularly useful when there is a biomarker that can be identii ed in the short term that predicts response to long-term treatment
Evidence that an association is cause and effect
What aspects of the research findings support cause and effect when only observational studies are available? In 1965, the British statistician Sir Austin Bradford Hill proposed a set of observations that taken together help to establish whether a relationship between an environmental factor and disease is causal or just an association.
Cause precedes effect
large relative risk
larger exposure to cause association with higher rates of disease
Reduction in exposure is followed by lower rates of disease
Repeatedly observed by different persons, in different places, circumstances and times
Makes sense according to biologic knowledge of the time
one cause leads to one effect
Cause and effect relationship already established for a similar exposure of disease
Definition of surrogate endpoint
A biomarker that is intended to substitute for a clinical endpoint. A surrogate endpoint is expected to predict clinical benei t or harm or lack of benei t or harm based on epidemiologic therapeutic pathophysiologic or other scientii c evidence. Surrogate endpoints are a subset of biomarkers. h e term surrogate literally means ‘substitute of ’ therefore the NIH working group discourages the use of the term surrogate marker because it suggests the substitution is for a marker rather than for a clinical endpoint.
Reasons why a surrogate endpoint may fail to be valid
h e i rst is that the surrogate outcome is not in the causal pathway between the disease and the true clinical outcome. h e second, related, possibility is that there is more than one causal pathway and the potential surrogate is only relevant to one of these pathways. h e third possibility is that the surrogate is not in the pathway of the intervention, or is insensitive to it. Finally, the intervention may have a mechanism of action that is independent of the disease process. h is last scenario may be most commonly observed in the case of (potentially harmful) side ef ects of treatment. A i t h possibility proposed by Frank and Hargreaves is that the biomarker may be overly sensitive and not correlated with a meaningful clinical phenotype [ 9 ] . In this case, improvements in the biomarker may be demonstrated, but would not be associated with health benei ts.
Considerations for developing drug in pediatric population
The decision to proceed with a pediatric development program for a medicinal product, and the nature of that program, involve consideration of many factors, including:
* The prevalence of the condition to be treated in the pediatric population
* The seriousness of the condition to be treated
* The availability and suitability of alternative treatments for the condition in the pediatric population, including the efficacy and the adverse event profile (including any unique pediatric safety issues) of those treatments
* Whether the medicinal product is novel or one of a class of compounds with known properties
* Whether there are unique pediatric indications for the medicinal product * The need for the development of pediatric-specific endpoints
* The age ranges of pediatric patients likely to be treated with the medicinal product
* Unique pediatric (developmental) safety concerns with the medicinal product, including any nonclinical safety issues
* Potential need for pediatric formulation development Of these factors, the most important is the presence of a serious or life-threatening disease for which the medicinal product represents a potentially important advance in therapy. This situation suggests relatively urgent and early initiation of pediatric studies.
Alternative hypothesis
The alternative hypothesis is closely aligned with the research hypothesis. The objective of the test is to seek evidence against the null hypothesis as a way of bolstering the alternative hypothesis, and thus the research hypothesis.
P value
We convert the z-statistic to a probability statement called the P-value. The P-value answers the question: “If the null hypothesis were true, what is the probability of the observed test statistic or one that is more extreme?” A small P-value indicates that observed data are unlikely to have come from the distribution suggested by H0.
One sample z-test
The one-sample z-test compares a mean from a single sample to an expected value. Several conditions must exist for the test to be used. These include: • The variable must be quantitative. • Measurements must be valid. •Data must be derived by an SRS or reasonable approximation thereof.
The standard deviation of the population (σ) must be known prior to data collection. •The sampling distribution of is approximately Normal.
Type 1 error
an erroneous rejection of a true null hypothesis
Type 2 error
an erroneous retention of a false null hypothesis
Confidence interval
Each of these confidence intervals has a 95% chance of capturing the population’s true mean weight μ.
What does confidence mean
What confidence means. The confidence level of an interval tells you how often the method will succeed in capturing μ in the long run. With repeating samples, (1 − α)100% of the intervals will capture μ and (α)100% will not.
Confidence interval reflects what?
Confidence interval length reflects the precision of the estimate. Narrow intervals reflect precision; wide intervals reflect imprecision.
Relationship Between Hypothesis Testing and Confidence Intervals
You can use a (1 − α)100% confidence interval for μ to predict whether a two-sided test of H0: μ = μ0 will be significant at the α-level of significance. When the value of the parameter identified in the null hypothesis (μ0) falls outside the interval, the results will be statistically significant (reject H0).
Accuracy
The accuracy of the measurement refers to how close the measured value is to the true value. It is otherwise called validity.
Precision
On the other hand, precision refers to how close a set or a group of measurements are together, which is otherwise called reliability.
Student t-distribution
When the sample size is small, the central limit theorem does not hold well. Exact sampling distributions are often derived for inferring from small samples. A classical example of the exact sampling distribution is Student’s t-distribution, which characterizes the sample mean for small samples.
Adverse event
An adverse event (AE), as defined by Good Clinical Practice, is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease
having been absent at baseline, or, if present at baseline, appears to worsen AND is temporally associated with medical treatment or procedure, REGARDLESS of the attribution (i.e., relationship of event to medical treatment or procedure).
Adverse Event: FDA Definition
FDA defines an adverse events as any untoward medical occurrence associated with the use of a drug in humans,
whether or not considered drug related.
Phase II
Phase II studies may be designated ‘Phase IIa’ or ‘Phase IIb’. Phase IIa usually indicates a single-arm trial designed to show initial evidence of clinical efficacy (‘proof of concept’). Phase IIb indicates a more reliable assessment of efficacy in a larger number of patients, often randomized with a control therapy group.
Excerpt from: “Fast Facts: Clinical Trials in Oncology: The fundamentals of design, conduct and interpretation” by A. Hackshaw. Scribd.
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Pick the winner
With this design, patients are randomly allocated to two or more experimental treatment arms, which could be for different drugs, combinations of drugs or doses of the same drug. The primary aim is to see which group has the highest response or most favorable markers of activity/efficacy, rather than to directly compare the experimental arms. The chosen arm (sometimes two arms) is likely to become the treatment arm for future trials, taking toxicity into account. Two-stage designs can also be used.
Excerpt from: “Fast Facts: Clinical Trials in Oncology: The fundamentals of design, conduct and interpretation” by A. Hackshaw. Scribd.
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Placebo in phase II
Use of a placebo can strengthen Phase II trial results and conclusions, especially when there are subjective endpoints (for example, tumor response and disease progression) that can be influenced by the lack of blinding in open-label trials. However, the cost of producing and distributing placebo in a Phase II trial may outweigh the scientific benefits, and investigators accept the potential for bias, with the intention of using placebo in a subsequent Phase III study.
Excerpt from: “Fast Facts: Clinical Trials in Oncology: The fundamentals of design, conduct and interpretation” by A. Hackshaw. Scribd.
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Basket trial
Basket trials involve testing a single drug targeted at a specific marker (for example, a mutation) in several tumor types or subtypes (one drug in several cancers).
Excerpt from: “Fast Facts: Clinical Trials in Oncology: The fundamentals of design, conduct and interpretation” by A. Hackshaw. Scribd.
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Umbrella trial
Umbrella trials categorize patients with a single tumor type into different groups according to a biomarker or mutation; each group receives a targeted agent for that biomarker (several drugs in one cancer).
Excerpt from: “Fast Facts: Clinical Trials in Oncology: The fundamentals of design, conduct and interpretation” by A. Hackshaw. Scribd.
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Analysis of single and pick the winner trials
Single-arm and ‘pick the winner’ randomized trials require mainly descriptive analyses, in which the efficacy endpoint data are summarized for each group separately.
Excerpt from: “Fast Facts: Clinical Trials in Oncology: The fundamentals of design, conduct and interpretation” by A. Hackshaw. Scribd.
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Target validation
Employing genetically modified animals for target validation is an appealing methodology as it permits the scrutiny of the phenotypic consequences of gene manipulation. Development of knock-outs, knock-ins, conditional knock-outs, and transgenic animals are instances of genetically modified animals.
Excerpt from: “Pharmaceutical Medicine and Translational Clinical Research” by Academic Press. Scribd.
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Allosteric modulation
Allosteric modulation of drug targets is another novel approach towards drug discovery, wherein drugs bind at binding sites of the biological target—which are distinct from the active sites. A benefit with this approach is that while active sites might be common in several proteins, the allosteric sites might be unique, which allows for selective targeting and consequently either fewer or target-specific adverse effects.
Excerpt from: “Pharmaceutical Medicine and Translational Clinical Research” by Academic Press. Scribd.
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DSUR
The Development Safety Update Report (DSUR) is used to provide periodic safety information during preapproval and for marketed drugs that are under further study, and the Periodic Safety Update Report (PSUR) is intended to provide an evaluation of the risk-benefit balance of a medicinal product at defined time points during the postapproval phase.
Excerpt from: “Pharmaceutical Medicine and Translational Clinical Research” by Academic Press. Scribd.
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AEDR
Adverse event data review
dominant negative mutations
the product encoded by the mutated gene
adversely affects the usual gene product within the same cell (for example, in
Marfan syndrome, the abnormal fibrillin-1 protein encoded by the mutant allele
interferes with the protein encoded by the normal allele, with widespread effects
on connective tissue)
gain-of-function mutations
he encoded protein new or enhanced
activity (for example, gain-of-function mutations in STAT1 and STAT3, which en-
code signal transducer and activator of transcription 1 and 3, have been impli-
cated in different clinical phenotypes, including chronic mucocutaneous can-
didiasis, increased occurrence of viral, fungal and bacterial infections, and au-
toimmunity)
Gene silencing can be used in what diseases?
gain-of-function diseases to inhibit the func-
tioning of a mutated protein and so ameliorate disease symptoms. Certain classes
of silencing agent can also be used to produce truncated proteins that bypass the
pathogenic genetic information, producing a semifunctional copy of the affected
gene via exon skipping.
RNA interference
RNA interference (RNAi) can lead to the highly specific targeted knockdown of ex-
pression of a disease gene. RNAi is typically mediated by either chemically synthe-
sized double-stranded siRNA or vector-based short hairpin RNA (shRNA). Besides
more efficient and targeted delivery, the added advantages of shRNAs over siRNAs
are linked to enhanced specificity and the ability to use promoters to drive in-
ducible expression.
Mechanism of RNA interference
RNA interference (RNAi)-induced post-transcriptional
gene silencing. Viral vectors deliver short hairpin (sh)RNA transgenes into the nu-
cleus for expression and processing by the Drosha enzyme. The shRNA is exported
into the cytoplasm via exportin 5. Association with the Dicer enzyme leads to re-
moval of the loop sequence and a small interfering (si)RNA is produced. siRNAs
can also be directly delivered into the cytoplasm as synthetic short duplexes
through endocytosis. However it is generated, the siRNA is recognized by Dicer
and primed to associate with RNA-induced silencing complex (RISC). This acti-
vates argonaute, the RNAse component of the RISC, leading to destruction of one
of the RNA strands. Through design, the remaining single-stranded RNA will bind
to complementary messenger (m)RNA, forming a double-stranded RNA that
undergoes RISC degradation, resulting in targeted knockdown of the gene.
Two ways to use antisense
oligonucleotides to inhibit gene expression.
One is to target critical regulatory re-
gions, such as the translational start codon of the mature mRNA or the polyadeny-
lation signal in the 3’ UTR. An alternative method for inhibiting gene expression
would be to design antisense oligonucleotides to skip exons to result in an out-of-
frame transcript. This brings a PTC into frame, resulting in NMD of the transcript
and knockdown of pathogenic protein expression.
Targeting non-coding RNA
Small non-coding (nc)RNAs – miRNAs – and long
non-coding (lnc)RNAs can be used alone or together to regulate transcription and
post-transcriptional processes and to direct chromatin-modifying complexes.⁴
Chromatin regulates gene expression and normally acts to inhibit gene expression
through condensation of the DNA. Short (21–23 nucleotides) double-stranded
miRNAs manipulate gene expression in a similar way to siRNAs (see Figure 2.1) –
they act to silence gene expression through the degradation of RNA and prevention
of translation. An siRNA targets a single gene, while an miRNA has multiple gene
targets.
Do viral vectors for gene therapy cross the BBB?
A feature of some AAV (adeno-associated virus)
serotypes
Neuronal specificity of viral vectors?
A feature of some AAV
serotypes
Can help avoid
glial-cell-mediated immune
response
Packing capacity of viruses
Adenovirus 7.5 kb
AAV 4.5 kb
Herpesvirus >30 kb
Lentivirus 8 kb
Advantages of adenovirus
- DNA genome episomally resides in host nucleus, preventing insertional
mutagenesis - Oncolytic*
- Vaccination†
- Able to transduce quiescent and proliferating human cells
- Strong immunogenicity – can enhance antitumor immunity and therapeutic
efficacy - Possible to produce 10–50 L
Advantages of AAV
- Capsid determines tropism and transduction profile in different cell types
- AAV9 can cross the blood–brain barrier and transduce cells of the CNS
following a single iv injection - Can transduce both dividing and non-dividing cells
- Recombinant viral genome stays in host nucleus, predominantly as episome
- Single or multiple copies of vector genome can circularize in head-to-tail or
head-to-head configurations in host nucleus, enhancing stability of the episomal
viral DNA genome and mediating long-term transgene expression in non-dividing
cells (e.g. muscle fibers) - No known disease associated with infection
- Low toxicity
- Long-term expression
Advantages of Herpes Simplex Virus
- Efficient infectivity in multiple cell types
- Naturally neurotropic‡
- Valuable for oncolytic virotherapy
- Has carrying capacity for multiple genes
Advantages of retroviruses
- Effective integration into target cell chromatin
- Envelope glycoproteins amenable to genetic modification to specify tissue
and/or tropism - Genomic integration ensures the stability of transgene and persistent transgene
expression in daughter cells following genome replication and cell division - Production can be scaled up and preparations banked (RCR free)
Advantages of Lentiviruses
- Efficient transduction in non-dividing cells
- Long-term expression
- Application in adoptive T-cell platforms
- Envelope glycoproteins amenable to genetic modification to specify tissue
and/or tropism - Genomic integration ensures the stability of transgene and persistent transgene
expression in daughter cells following genome replication and cell division - Large-scale clinical production possible
*Infect and kill tumor cells.
†High immunogenicity induces a strong humoral T-cell response, tending toward
a T helper 1 type response, to the transgene expressed by the vector.
AAV, adeno-associated virus; CNS, central nervous system; iv, intravenous.
‡After initial infection via skin or mucous membranes, herpes simplex virus is
taken up by sensory nerve terminals, travels along nerves to neuronal cell bodies
and delivers its DNA genome into nuclei for replication.
RCR, replication-competent retrovirus.
Disadvantages of adenoviruses
- Pre-existing immune and inflammatory response
- Complex for manipulation
Disadvantages of AAV
- T-cell response
- Antibody neutralization
- Low DNA packaging capacity
- Complex downstream processing complicates manufacturing
Disadvantages of herpes viruses
- Lack of long-term expression
- Poor patient experience
- Low titers limit large-scale production
Disadvantages of retroviruses
- Insertional mutagenesis
- Limited ex vivo application
Disadvantages of lentiviruses
- Insertional mutagenesis
- Limited cassette size
AAV, adeno-associated virus.
Major risk of AAV?
The major risk factor associated with adenoviral vectors is
the strong immune neutralization against the standard serotypes used. This could
be bypassed with adenoviral vectors derived from other primate species and these
are now being explored.
Certain serotypes of AAV vectors have restricted patient applicability; previous
infectious exposure to the viral capsid proteins results in seropositive neutralizing
antibody. Rare AAV serotypes are being identified and artificial serotypes engi-
neered to overcome this problem.
Transgene expression
The maximal therapeutic efficacy of a gene therapy is
achieved through controlled targeted expression, with the avoidance of side effects
associated with off-target and non-physiological expression. Modification of
tropism displayed by a vector is possible through engineering of the viral vector
surface proteins, together with the use of tissue-specific promoters. It is also pos-
sible to include elements within the expression cassette that allow regulation by the
host cell itself or that provide drug-inducible expression. It should be noted that
unique features, either structural or biochemical, displayed by diseased cells can
be exploited to restrict expression to where it is needed.
Basket trial
Basket trials refer to designs in which a targeted therapy is evaluated on multiple diseases that have common molecular alternations.
Umbrella trial
Umbrella trials, on the other hand, evaluate multiple targeted therapies for a single disease that is stratified into subgroups by molecular alternation.
Types of bias
ITT
In an ITT analysis, the study treatment group includes all patients who were assigned (usually randomized) to that study treatment group, even those who dropped out or received incomplete or inaccurate doses of the treatment. Even patients who never received a single dose of the treatment belong in the study group. There is a saying to describe ITT: “analyze as randomized.” So once patients are randomized, they are “stuck” in the analysis. Nothing that happens after randomization (e.g., noncompliance, protocol deviations, or dropping out) can exclude them being included in the analysis.
mITT
A modified ITT analysis includes all randomized patients that meet a specific minimum standard or simple set of criteria. The criteria should be simple, objective, and very straightforward. The criteria should not be related to the outcome (e.g., if you know that patients with lower socioeconomic status will be less likely to respond to your intervention, you cannot use socioeconomic status as a criterion). Using subjective criteria defeats the purpose of a modified ITT. The more common modified ITT will include all patients who received at least one dose of the study intervention (regardless of what happened to the patient after the initial dose). The study protocol should pre-specify a modified ITT analysis and its criteria. Otherwise, selection bias can occur (e.g., if you find that a certain characteristic correlates with poor intervention response, you could later exclude patients with that characteristic from the analysis.) Another common modified ITT analysis excludes all patients who had major protocol violations (e.g., did not meet the study selection criteria). Usually the primary analysis should be an ITT analysis, but in some rare cases (e.g., noninferiority or equivalence trials), a modified ITT may be appropriate.
Measuring CNS exposure and target engagement
MAD studies
When conduct phase I in patients
Dose response
FDA guidance
Max tolerated dose
Per protocol analysis
Unlike ITT analysis, per protocol analysis only includes patients who successfully adhered to the protocol (i.e., no major protocol violations). In many cases, per protocol analysis may serve as the primary data analysis (for clinical trials, FDA approval may be necessary). The major strength of per protocol analysis is the weakness of ITT analysis: it removes significant noise from study, noise that may prevent you from truly determining an intervention’s effects. Conversely, we covered the major weaknesses of per protocol analysis when discussing the strengths of ITT analysis.
Aim of single ascending dose studies?
he key objectives of single ascending dose stud- ies are to deine safety, tolerability, pharmacokinet- ics and pharmacodynamics of a drug. he dose range deployed usually covers approximately two logs and is framed by a starting dose that is a fraction of the preclinical pharmacologic no-pharmacologic efect dose (NOPED) in the most appropriate or sensitive species and limited to a top dose that is guided by the preclinical exposure (drug concentration in plasma) at the no-adverse efect level (NOAEL)
NOAEL
no-observed adverse effect level
MAD studies
Multiple ascending dose studies extend observa- tions on human pharmacology to longer periods of dosing. Again, the key objectives are to provide data on safety, tolerability and pharmacokinetics with pro- longed dosing. In most studies, the duration of dosing ranges from 7 to 14 days with dosing frequency deter- mined by the pharmacokinetic parameters deined in single-dose studies. Typically, 4–5 dose levels are examined in the single ascending dose study, with the dose range covering a little over 1 log.
What kind of studies are first conducted in patients in early development?
Some initial studies in humans can only be con- ducted in patients. Medications with substantial poten- tial toxicity risks such as cytotoxic or genotoxic drugs cannot be administered to normal volunteers and for this reason, early studies are conducted in patients. he most common setting where this occurs is in oncology drug development where initial single- and multiple- dose studies are virtually always conducted in cancer patients. Examples from neurological therapeutics include the use of speciic B-cell depleting therapies for multiple sclerosis and immunotherapeutic vaccines for A l z h e i m e r ’s d i s e a s e [ 1 , 2 ] .
What is critical to characterize during middle stage development?
During middle stage development it is critical to begin to characterize the dose-response relationship for eicacy and safety endpoints in the selected popula- tion. Determination of the likely efective and safe dose range is a critical objective of middle stage develop- ment that afects not only the design of later stage trials but other aspects of non-clinical development as well. An important study from the FDA showed that a sub- stantial percentage of new drugs approved were rela- beled to correct dose ranges, and the majority of these changes were for safety reductions [10]. Of all thera- peutic areas examined, drugs for nervous system indi- cations had the highest percentage of dosing changes. Establishment of the optimal dose range requires that substantial attention be paid to selection of the appro- priate patient population, eicacy endpoints, and safety evaluations.
How are PROs evaluated by regulators?
Regulatory agencies review and evaluate the suitability of PRO assessments based upon several characteristics including the medical condition and population for intended use, concepts being measured, number of items, conceptual frame- work, data collection method, scale administration, response options, scoring and weighting of items or domains, and availability of translations or cultural adaptations.
What is important regarding PRO development?
Because the properties of a measurement instru- ment like a PRO need to be well understood prior to collecting deinitive eicacy data in pivotal conirma- tory trials, this important groundwork must be initi- ated and is oten largely completed during middle stage development. he FDA has published a useful guidance document that is aimed at ensuring that the process for evaluating new instruments is adequately understood by clinical researchers
NOAEL
The common definition of NOAEL, “the highest experimental point that is without adverse effect,”
Lowest Observed Adverse Effect Level (LOAEL)
Lowest Observed Adverse Effect Level (LOAEL) is the lowest exposure level at which there are biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control group.
Problems with historical control
Historical controls: may have received difering concomitant therapies; may have been treated by diferent physicians, using diferent protocols to manage therapy; may not have met all inclusion criteria for current study; may have difering distributions of prognostic factors
Common types of bias
Selection bias occurs when there are systematic differences between groups. For example, if groups are not comparable on key demographic factors, then between-group differences in treatment outcomes cannot necessarily be attributed solely to the study intervention. RCTs attempt to address selection bias by randomly assigning participants to groups – but it is still important to assess whether randomization was done well enough to eliminate the influence of confounding variables.
Performance bias refers to systematic differences between groups that occur during the study. For example, if participants know that they are in the active treatment rather than the control condition, this could create positive expectations that have an impact on treatment outcome beyond that of the intervention itself. Ideally, participants and investigators should remain unaware of which group participants are assigned to. Of note, this is more easily achieved in medication trials, where the medication and the placebo appear identical, than in psychotherapy trials.
Detection bias refers to systematic differences in the way outcomes are determined. For example, if providers in a psychotherapy trial are aware of the investigators’ hypotheses, this knowledge could unconsciously influence the way they rate participants’ progress. It is crucial that psychotherapy RCTs address this by utilizing independent outcome assessors who are blind to participants’ assigned treatment groups and investigators’ expectations.
Attrition bias occurs when there are systematic differences between groups in withdrawals from a study. It’s common for participants to drop out of a trial before or in the middle of treatment, and researchers who only include those who completed the protocol in their final analyses are not presenting the full picture. Analyses should include all participants who were randomized into the study (intention to treat analysis), and not only participants who completed some or all of the intervention.
Reporting bias refers to systematic differences between reported and unreported data. One example is publication bias, which occurs because studies with positive results are more likely to be published, and tend to be published more quickly, than studies with findings supporting the null hypothesis. At the investigator level, outcome reporting bias can also occur when researchers only write about study outcomes that were in line with their hypotheses. Efforts to address this include requirements that RCT protocols be published in journals or on trial registry websites, which allows for confirmation that all primary outcomes are reported in study publications.
Other bias is a catch-all category that includes specific situations not covered by the above domains. This includes bias that can occur when study interventions are not delivered with fidelity by therapists, or when there is “contamination” between experimental and control interventions within a study (for example, participants in different treatment conditions discussing the interventions they are receiving with each other).
How to select FIH dose
The EMA and the FDA have published guidance documents for investigators to follow when determining an appropriate starting dose. The EMA guidance assists in the transition from preclinical to early clinical development and covers many of the risks inherent to FIH trials and discusses mitigation strategies to manage these risks.2 The FDA guidance aims at avoiding toxicity at initial doses by using the generally accepted benchmark for safety, the NOAEL obtained from the most sensitive toxicology test species as a starting point for determining a reasonably safe starting dose.1
Method of selecting FIH dose
Methods for calculating the starting dose are either empirical or mechanistic (Table 2). As mentioned, the most widely used empirical method follows the FDA guidance1 for estimating a maximum safe starting dose by converting the NOAEL to a human equivalent dose with the use of allometric scaling. However, this method has its disadvantages, including the use of a somewhat arbitrary safety factor to ensure safety of the starting dose, the dose is based on minimal risk of toxicity rather than based on pharmacologic activity, and it does not address dose escalation or the maximum allowable dose. The EMA guidance2 outlines a more mechanistic approach based on state-of-the-art modeling incorporating all relevant preclinical pharmacology data including ex vivo and in vitro studies in human tissues. This guidance highlights selection of a minimal anticipated biological effect level, as this is becoming increasingly important as more targeted therapies are being developed that are very specific and potent with predicted pharmacologically active doses well below a dose that is thought to be safe based on the NOAEL.11
Biomarker in phase 1
The FIH study represents the first opportunity that a biological readout can be obtained in humans. The measurement of biomarkers in conjunction with a drug treatment could be important both during drug development and clinical implementation after marketing approval. Biomarker readouts can help guide drug development: from discovery through target engagement assessment, to diagnostic use, and on to the promise of precision medicine and companion diagnostics in everyday clinical practice.
Validity
Validity is a more complicated topic than reliability. Validity refers to the degree of correspondence between a test score and the construct (e.g., “hopelessness”) or diagnosis (e.g., “panic disorder”) that it was designed to measure. The absence of true gold standards for measuring psychiatric condition makes assessing validity even more difficult in our field. It may be best to think of validity as indicating the accuracy of a score. Basic forms of validity include content validity, criterion validity, and construct validity.
