Early Drug Development: Strategies and Routes to First-in-Human Trials

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Khan noted that many common reasons can lead to a clinical hold of an IND application.

Non-clinical studies that are irrelevant or inadequate are two possible reasons. Inadequate studies might lack sufficient documentation, test too few animals, not assess standard parameters or not provide data, study inadequate doses, use a route of administration other than that proposed for the humans without justification, and have had an insufficient duration. Another common reason for a clinical hold is that a no-effect dose for serious toxicity was or could be determined.

Serious toxicity with no or an inadequate strategy for monitoring the toxicity in humans could warrant a clinical hold as well. In addition, problems with CMC that require non-clinical safety testing e. Lastly, if the clinical investigator has an inadequate brochure, then that could lead to a clinical hold, said Khan.

In some cases, a clinical hold may be avoided, said Khan. For example, a sponsor can revise the clinical protocol to limit the dose to provide a sufficient safety margin e. In other cases, the sponsor can submit scientific justification to support the original clinical protocol. For example, for inadequate high-dose selection in a pivotal toxicity study, the sponsor can provide data to document that the toxicity is not relevant to humans. Khan emphasized that when protocols depart from standard testing requirements, justification is necessary.

Drug discovery

When asked to explain the animal rule for IND applications, Bastings explained that animal studies are needed only when human efficacy trials are neither feasible nor ethical. In some cases, a risk—benefit analysis is needed for protocols in which animal efficacy models may be needed. Bastings added that, typically, animal models are not required for INDs to be tested in clinical trials.

Bastings and Khin stressed the importance of case-by-case decision making regarding regulatory requirements and reiterated the importance of a pre-IND meeting for discussion of the elements of a successful IND. Several participants inquired about the regulatory process for therapeutics that could potentially treat serious or life-threatening disorders. The first is known as Fast Track, which applies to drugs intended for serious diseases or that fill an unmet need.

The unmet need criterion is defined as providing therapy where none exists or providing therapy that may be potentially superior to existing therapies FDA, b. The process for receiving a Fast Track designation is expedited in the following ways: more frequent meetings with FDA, more frequent written correspondence, and a rolling review process, which allows a sponsor to submit portions of its NDA before the rest of its submission.

Normally, FDA requires that the entire package be submitted together. Breakthrough therapies can take advantage of all the features of the Fast Track designation plus more intensive guidance from FDA on an efficient drug development program. These additional features include holding meetings throughout the different drug development processes, ensuring that the design of clinical trials is as efficient as possible, and assigning a cross-disciplinary project lead for the FDA review team to facilitate review.

Many participants noted that there is complexity and a lack of clarity in the IND application process. Khin directed participants to the FDA website to find guidance on the process; however, Khin noted that the guidance is non-binding. A participant stated that there has been a transition from traditional efficacy studies using animals to select efficacy studies when there are sufficient safety data and a plausible mechanism.

The field is developing tools to better understand the molecular level of a disease and move toward a patient-stratified approach with the goal of developing compounds with less toxicity. The participant concluded with an open question about whether the IND application process would be different for these cases. Robert Conley, regulatory leader of Biomedicines at Eli Lilly and Company, offered several thoughts on how to improve communication and reduce regulatory delays. Conley first observed that startups and small drug companies seem to be afraid of communicating with FDA.

These meetings can help to explain the basis for regulatory requirements. Next, Conley observed that increased harmonization of requirements among FDA divisions might lead to a better understanding of requirements by applicants and, therefore, higher rates of and faster times to acceptance. Problems with conflicting or divergent requirements occur most frequently with drugs for which a new indication is sought. For example, the safety pharmacology requirements might differ between nervous system drugs and cardiovascular drugs, making it necessary for the sponsor to conduct an unexpected new round of pharmacological testing.

The time and expense might be too great for a fledgling sponsor.

If an impasse is reached between FDA and a sponsor, then it is important to learn from the experience, said Conley. Laws, regulations, and guidance drive. FDA culture; it is not driven by the standards of merit that typically apply to the academic community. Conley asserted that academics and industry tend to argue too vehemently for their own points without understanding the constraints under which FDA operates. The current drug development pipeline is multifaceted and complex, composed of great risk that a drug will not be successful even after many resources have been invested.

Nervous system disorder drugs in particular face a number of challenges that complicate drug development even further. Although regulatory processes are not intended to hinder drug development, many investigators are unclear of the specific requirements for INDs and request comprehensive guidance. Opportunities to improve and accelerate drug development for nervous system disorders through emerging new tools and technologies, novel methodological approaches, and infrastructural changes is explored in subsequent chapters. Improving and Accelerating Therapeutic Development for Nervous System Disorders is the summary of a workshop convened by the IOM Forum on Neuroscience and Nervous System Disorders to examine opportunities to accelerate early phases of drug development for nervous system drug discovery.

Workshop participants discussed challenges in neuroscience research for enabling faster entry of potential treatments into first-in-human trials, explored how new and emerging tools and technologies may improve the efficiency of research, and considered mechanisms to facilitate a more effective and efficient development pipeline.

There are several challenges to the current drug development pipeline for nervous system disorders. The fundamental etiology and pathophysiology of many nervous system disorders are unknown and the brain is inaccessible to study, making it difficult to develop accurate models. Patient heterogeneity is high, disease pathology can occur years to decades before becoming clinically apparent, and diagnostic and treatment biomarkers are lacking. In addition, the lack of validated targets, limitations related to the predictive validity of animal models - the extent to which the model predicts clinical efficacy - and regulatory barriers can also impede translation and drug development for nervous system disorders.

Improving and Accelerating Therapeutic Development for Nervous System Disorders identifies avenues for moving directly from cellular models to human trials, minimizing the need for animal models to test efficacy, and discusses the potential benefits and risks of such an approach.

This report is a timely discussion of opportunities to improve early drug development with a focus toward preclinical trials. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website. Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

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Lisa Hutchinson

Note that regulatory authorities hold both parties responsible for meeting cGMP requirements. Small pharma as well as CDMOs are not of a single character. From the CDMO point of view, clients seem to come in at least three types:. Contract organizations also cover a range; the extremes perhaps being the larger CDMOs that can deliver excellence in Phase 3 and commercial manufacturing and, on the other end, the usually smaller organizations that excel in science and collaborative working relationships with clients. Of course, between these extremes are many organizations that seek and achieve some measure of success in both disciplines.

The best small pharma-CDMO relationships are those in which both partners accurately perceive the strengths of their union, and do not hesitate to seek assistance from other sources to address weaknesses. Another challenge in this paradigm regards the personnel involved. This makes sense from a resource point of view; however, small pharma should recognize the risk this plan creates as the CMC tasks multiply. On the CDMO side, at least two difficulties exist: the first being to attract the highest-caliber scientists into an environment that has enough scientific opportunity to retain these scientists, and the second being to develop a broad-base of experience for their scientists that results in an understanding of CMC development strategy, not just the associated tasks.

The summary of the personnel challenge is that often, neither the small pharma nor the CDMO have the scientists on-board to guide CMC programs from a broad base of relevant experience. One possible reason that CDMOs may have difficulty taking advantage of this guidance is the considerable risk of trying to maintain different levels of cGMP compliance within a single organization. Taking full advantage of these meetings, especially a dedicated CMC End of Phase 2 meeting and a pre-NDA meeting, is one key to an efficient development strategy. Table 2 lists EMEA documents relevant to clinical phase development of new pharmaceuticals.

In particular, the March guidance on Investigational Medicinal Products IMPs offers useful details on what information is expected to be provided. Examples of regulatory authorities requiring sponsors to address limits and tests for potentially genotoxic or carcinogenic impurities are familiar to most regulatory scientists. The phase-appropriate aspect is that both authorities have a staged limit on genotoxic and carcinogenic impurities, according to the duration of the clinical study.

The ICH guidances are frequently referenced by small pharma and CDMOs for topics such as method validation and impurity specifications. Whether by contract organization or sponsor, the rationale appears to be that without quantitative guidances applicable during clinical development, a safe stance is to apply the relevant ICH standard. For example, impurity specification is a common area where ICH limits are often quickly applied during early clinical development.

The small pharma organization may not have the regulatory and safety assessment resource to develop a sound policy on acceptable impurity levels during clinical development — with the result that ICH limits are applied during early development. The genotoxic impurity topic is almost unique in this regard, having established impurity limits tied to duration of clinical studies.

These strategies are described across two dimensions: the properties of the active substance and the functional areas of synthetic, formulation and analytical science. While there are many properties of the active substance that can influence CMC strategy for small pharma, an obvious group of properties to consider are those embodied in the Biopharmaceutical Classification System BCS for oral drugs first described by Amidon et al.

Consider the case of a BCS I compound, noting that regardless of the absolute value of its solubility, what matters is dose solubility.

In early phase work, there is often considerable uncertainty about the safe and effective dose, and more than one BCS category might be possible. The short message is that formulation approaches for such a drug assuming no other issues such as stability have significant latitude and flexibility during development.

An acquiring company or partner could change the dosage form composition or process with minimal risk up to Phase 3. So the CMC development strategy for small pharma should be to not over-develop the formulation for this asset for early clinical studies, as this effort adds little to the value of the overall program, which will be driven by safety and efficacy. In contrast, consider a BCS II compound, particularly one that is strongly challenged in terms of solubility.

Here, the development of a dosage form that reliably generates useful human exposure may contribute significantly to the value of a development asset. In this situation, the earlyphase small pharma company should demonstrate to potential partners that a methodical, science-driven approach to formulation has occurred and that formulation issues are solvable. In the synthetic area, three strategies are offered for consideration.

This guidance recommends that manufacturers document the starting materials and reagents used in the synthesis of drug substance used in initial Phase 1 clinical studies, but stops short of recommending batch records. Some organizations have adapted their processes to document in laboratory records all of the information normally expected for cGMP synthesis, but to do so in a laboratory notebook or equivalent record. Then at the last or next-to-last synthetic step, more typical GMP controls e.

The hypothesis that this cell type also exists, and is functionally similar, in damaged skin was tested and, with the characteristics of chemokines in mind, the idea was born to use lactic acid bacteria as vectors to deliver CXCL12 to the site of wounds. She also holds a BSc degree in management accounting from , and an MBA specialising in finance and mergers and acquisitions from Preclinical decisions for clinical development The entire process of moving a drug from idea in a preclinical lab to clinical trials and approval takes a long time.

The preclinical data will be important during the whole lifespan of the drug and especially for drugs that expands e. Deciding whether a drug is ready for clinical trials involves extensive preclinical studies that yield preliminary efficacy, toxicity, pharmacokinetic and safety information.

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Just as with clinical trials, there are certain types of trials that in most cases have to be carried out, such as toxicology studies, and other trials that are specific to the particular study compound or question. Understanding that the goal of preclinical trials is to move into the clinical stage is key, and the studies should be designed around that goal.

IPPCR 2016: Concepts in Pharmaceutical Development Project Management

Currently, as director of SDS, he supports clients on both strategic and operational levels, particularly in the field of design and delivery of late preclinical and early clinical development. Klavs Esbjerg Epista Life Science. Proactive Quality Risk Management Growth, digitalization and patient-centricity: The Life Science industry is experiencing serious pressure and rapid change.

Many companies find regulatory compliance a major obstacle on their path to success. They ask serious questions about their compliance: - Are we over-spending on time and resources, hampering efficiency and our bottom line? Explore concrete ways to make the black box of compliance more transparent throughout the entire organisation. The business result: predict the impact of new initiatives, new regulations, and new technology on your quality efforts. And keep your efforts optimized — efficient and in-control.

We turn compliance obstacles into business opportunities for our clients and for the industry. Since , Klavs and his team have built Epista into an international business with over clients in Europe, US and Asia. This includes legal responsibility, sales as well as business development and delivery. Klavs has a degree in Chemical Engineering from the Technical University of Denmark as well as a management degree from Scandinavian International Management Institute.

Anders Sveno PledPharma. How to identify the appropriate CMO for CMC services Manufacture of pharmaceutical drug products is a complex process, including much more than the actual manufacture. Identification and development of a synthesis route as well as development of a suitable formulated drug product require many different disciplines to come together and collaborate. It is important to understand that the final delivery is not only the drug product itself but also a regulatory file, with enough data and detail to be accepted by the different health authorities.

For many years, both big pharma as well as small and medium size companies have outsourced significant parts of their CMC activities. Depending on the capabilities within the outsourcing company there are different requirements for how the appropriate CMO should be identified. Almost all projects he has been involved in over the years have been supported by significant outsourcing activities, covering CMOs from all over the world.