Being first to market with an innovator drug remains the ultimate goal for all, and most organisations are constantly reviewing timelines in order to achieve efficiencies through trial design, conduct and the reduction of downtime between phases of drug development. But clinical trials and drug development is an expensive and slow process, representing approximately 60% of project total development costs. In 2019 the cost of bringing a drug to market was estimated to be around £2.1 billion.
As a small biotech, how can you ensure that your asset is ahead of your competitors without the weight or budget of a larger organisation to support the process? In this article we will look at some of the strategies you can adopt during your nonclinical development to ensure your clinical development programme stays on track.
Firstly, it can be helpful to look at your development from a regulator’s perspective. Regulatory authorities, regardless of where they are in the world, are constantly balancing the need for new therapeutics with the negative consequences of an unsafe or ineffective pharmaceutical. It should also be recognised that regulatory guidelines are just that, guidelines. They do not necessarily represent the real world, and there can be more than one way to arrive at the same destination. As long as there is robust scientific justification for the path you follow to your submission, the regulators will always make decisions based on risk versus benefit, not on whether or not you followed guidelines to the letter.
The ultimate goal of nonclinical studies is not to prove that a drug is safe, you merely have to prove that it is acceptably safe to test it in humans. With this in mind, you should never conduct a nonclinical trial unless it will generate data that you can both interpret and that will be useful to your submission. Anything less is not only unethical, in terms of animal use, it is a waste of time and your budget.
Nonclinical safety data are usually very limited at the beginning of clinical development but must always be adequate to characterise potential adverse effects that might occur under the conditions of any clinical trial that you are hoping to support. The most appropriate nonclinical studies are based on extrapolation to indicate possible risks to humans, and are means to an end, not an end in themselves. You should always think ahead, the value of a toxicology study is only as good as its design.
Crucial to your success is that you identify and focus on the primary endpoint and be certain that this is the most appropriate endpoint to work towards. Getting side-tracked and distracted can result in the most appropriate endpoint being missed, which can have negative or even fatal consequences once you are in the clinical situation.
Consider the ICH M3 (R2) Guidance Document on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorizations for Pharmaceuticals, it tells you what to do and when to do it, but does not actually go into details of study designs. This document applies to situations that you will usually encounter during the development of a pharmaceutical, and this should always be viewed as a general guidance for drug development. There are other guidance documents which may also be appropriate, for example, biotechnology derived products, oncology products, etc., and for these types of products, ICH M3 only gives guidance on regards the timing of the studies, rather than what studies you have to do.
In principle, the duration of the animal toxicology studies, usually conducted in two mammalian species, one of which should be a nonrodent, should be equal to, or exceed the duration of the planned initial human clinical trials up to a maximum recommended duration.
The data generated from nonclinical studies are also important to the design of the early-stage clinical trials with respect to the clinical starting dose, the dose escalation plan, maximum dose, and the route of administration etc. But nonclinical studies will also, hopefully, provide findings that will help guide patient eligibility criteria, and also determine some important safety monitoring procedures.
Finally, don’t forget that nonclinical does not necessarily mean animal and a science-based, nonanimal approach in drug development is not only possible, but is recommended in many cases these days.
The bottom line is that an understanding of the overall clinical development plan is always needed to design and appropriate efficient nonclinical plan. Weight of evidence-based decisions should be made to determine whether additional nonclinical investigations are warranted; you should always have a good look at the information you have and ask yourself, do I need any additional nonclinical studies?
Healthy volunteer studies
Healthy Volunteer (HV) trials should be planned, and their designs should represent, an approach to a scientifically and ethically appropriate trial specifically for your drug. The decision to grant a Clinical Trial Authorisation (CTA) is based on safety considerations versus risk and the assumption that there is no such thing as a drug that is 100% safe – all drugs, even those which are authorised or in development, have some sort of risk. Regulators will always be asking themselves, do the data supplied support the use of this product administered in this way, in these doses, for the proposed duration, to this type of participant?
In the early part of 2022, the EU’s clinical trial regulation came into place, and it is now mandatory for all new clinical trials in Europe. That is of course, with the exception of the UK, since the UK will not be part of the Clinical Trials Regulation.
We now have the guideline on Strategies to Identify and Mitigate Risks for First in Human and Early Clinical Trials with Investigational Medicinal Products. Where previously a company would perform a single ascending dose (SAD) in healthy volunteers, sometimes in patients, then perform another clinical trial, looking at multiple ascending doses (MAD) and then a third clinical trial in patients, it is more common nowadays to perform SAD, or MAD in healthy volunteers and patients and/or special populations, all in one clinical trial.
In many ways, it is extremely easy to have a safe starting dose in a First in Human (FIH) clinical trial, but it is also necessary to get to a dose that is clinically meaningful. So careful selection of an Investigational Medicinal Product (IMP) is a vital element to safeguard the subjects, particularly in first human trials and then in early clinical trials.
All available nonclinical data should be taken into consideration in the calculation of the starting dose, the dose escalation, and the maximum dose, and this includes pharmacogenomics, pharmacokinetics, toxicokinetics, toxicology findings, and the dose/ exposure effect relationships, etc. The clinical data, once it starts emerging, should be considered in line with some pre-specified decision criteria. And obviously, if there are similar drugs with similar mode of actions, you can take this experience into account as well.
Generally speaking, although it is effectively a conservative estimate, the No Observed Adverse Effect Level (NOAEL) should be determined in a nonclinical safety study in the most relevant species and from this information you can work out an equivalent human dose. Estimations should be based on state-of-the-art modelling (e.g. PK/PD and PBPK) and/or using allometric factors. Exposure showing PD effects in the nonclinical pharmacology studies, including ex vivo and in vitro studies in human tissues if feasible, should also be determined. These data should be used to determine an estimation of the Pharmacologically Active Dose (PAD) and/or Anticipated Therapeutic Dose range (ATD) in humans. Some Sponsors also calculate the Minimal Anticipated Biological Effect Level (MABEL) in humans.
The calculation of the PAD, ATD and MABEL must also consider target binding and receptor occupancy studies in vitro using both target cells from human, and the relevant animal species, along with exposures at pharmacological doses in the relevant animal species.
The starting dose for the HV study should always be lower than the Pharmacologically Active Dose unless you can provide a rationale for starting at the PAD. Depending on the level of confidence in your nonclinical findings and your intended targets, the dose should be related to PAD, ATD or in extreme cases, MABEL. Regardless, both the Investigator Brochure (IB) and the protocol should contain robust scientific rationale for the starting dose selection. Safety factors can also be applied to the starting dose to further limit the risk of adverse events for HV. These should take into account the novelty of the active; if you are first in class you will require more of a safety margin than if you are fourth or fifth. Are the findings irreversible or long lasting? What is the shape of the dose response curve in your animal models? How relevant is the animal model? What is the totality of the nonclinical data? Are there any other uncertainties in the calculation of the starting dose? The findings in nonclinical studies may not be as easily monitored in HV studies. Once again, the reasoning behind the safety margins must be detailed in the protocol and the IB.
Moving into patients
Similar considerations as outlined for HV also apply to the identification of a safe starting dose in patients. The goal of selecting the starting dose for FIH/early clinical trials in patients, i.e., where there are no previous data in healthy volunteers, is to identify a dose that is expected to have a minimal pharmacological effect and is safe to use. The starting dose should also consider the nature of the disease under investigation and its severity in the patient population included in the clinical trial. In many instances, a starting dose for patients that is substantially lower than the human expected pharmacological dose may not be appropriate, and in the UK, it would be regarded as unethical to set a starting dose in a patient study that clearly did not have a pharmacological effect.
Once again, in all cases, a rationale should be provided, and the patients included in the clinical trial should be informed. If potential differences in target distribution, PK or safety profile of the IMP between HV and patients can be foreseen, consideration should be given to reverting to a SAD design (with dose escalation as appropriate) in the first patient cohort or starting at a dose that is lower than that identified as “safe” in HV.
Maximum exposure
An expected maximum exposure level, which should not be exceeded in the study without approval of a substantial amendment, should be pre-defined in the protocol for each study part (except for oncology products). The maximum exposure should be justified based on all available nonclinical and clinical data, including PD, PK, findings in toxicity studies, and exposure at the expected therapeutic dose range. Target saturation should be taken into account when appropriate, and the maximum exposure should consider when complete inhibition or activation of the target is achieved, such that no further therapeutic benefit is gained by increasing the dose
In general, the maximum exposure of healthy volunteers should be within the estimated human pharmacodynamic dose range. Exposure levels exceeding the pharmacodynamic dose range can, if scientifically justified and considered acceptable from a safety perspective, be carefully explored. For trials or trial parts that include patients, the Maximum Tolerated Dose (MTD) if applicable should be clearly defined and not be exceeded once it has been determined.
In such instances, the potential therapeutic/clinically relevant dose (exposure) and the expected benefit/risk balance should always be considered when defining the dose range. A trial design using an MTD approach is considered to be inappropriate for healthy volunteers.
Inclusion of women of childbearing potential
For Women of Childbearing Potential (WOCBP), there is a high level of concern for the unintentional exposure of an embryo or fetus before information is available concerning the potential benefits versus potential risks. The recommendations on the timing of reproduction toxicity studies to support the inclusion of WOCBP in clinical trials are similar but not identical in all ICH regions. WOCBP can be included in early clinical trials without non-clinical developmental toxicity studies under certain circumstances.
One such example is the intensive control of pregnancy risk over a short duration (e.g., 2 weeks) clinical trial. Another could be where there is a predominance of the disease in women and so the objectives of the clinical trial cannot be effectively met without the inclusion of WOCBP and there are sufficient precautions to prevent pregnancy.
Where precautions to prevent pregnancy in clinical trials are used, the inclusion of (up to 150) WOCBP receiving investigational treatment for a relatively short duration (up to 3 months) can occur before the conduct of definitive reproduction toxicity testing in the UK, some EU member states and in the USA.
All female reproduction toxicity studies and the standard battery of genotoxicity tests should be completed before inclusion, in any clinical trial, of WOCBP not using highly effective birth control or whose pregnancy status is unknown. The guidance provides clear recommendations but does not entirely rule out case-by-case deviations from the core recommendations if the sponsor can provide specific justification. European guidance on contraception is contained in the Clinical Trials Facilitation Group’s document Recommendations Related to Contraception and Pregnancy Testing in Clinical Trials
Information on the risks with exposure to the active substance before and during pregnancy and during lactation should be provided in the IB as well as recommendations on contraception and the management of risk in the clinical protocol.
Seeking advice
The MHRA has, for many years, provided scientific and regulatory advice to sponsors. Scientific advice can be requested during any stage of the initial development of the medicinal product (before submission of a Marketing Authorisation Application), and also during the pre-submission period for a variation to an existing marketing authorisation.
The MHRA helpline is a useful tool for asking regulatory/broad issue questions, and scientific advice can also be obtained from the EMA via the Committee for Medicinal Products for Human Use (CHMP). Their Scientific Advice Working Party (SAWP) has been established as a standing working party with the sole remit of providing Scientific Advice and Protocol Assistance to applicants. Note also that there is new section on the EMA website devoted to questions outside the scope of scientific advice.
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Article adapted from a webinar presentation by David Jones, Consultant, Regulatory Pharmaco-Toxicologist, ApconiX