10 Questions You Should to Know about Drug Discovery

Every Small Emerging Biotech with a Drug Development Program Should Ask at Year-End

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As an emerging biotech company, the end of the year is a critical time for reflection and strategic planning. This period offers an opportunity to evaluate the progress and direction of your drug development program. Here are ten essential questions to guide your year-end review, complete with examples to illustrate their importance:

1. Have We Met Our (CMC) Regulatory Milestones?

If your goal was to achieve Orphan Drug Designation for a novel therapy, assess whether this has been accomplished and understand the implications for your development timeline and funding opportunities.

Example: If your biotech was targeting a Breakthrough Therapy Designation for a new oncology drug, evaluate if the necessary CMC data met the FDA's thresholds. Consider the impact on your timeline if you did not meet these milestones, such as potential delays in Phase III trials or reassessing timelines.

2. Is Our Regulatory Strategy Still Relevant?

Consider if recent FDA guideline updates affect your strategy for an NDA/BLA or Special Designated submission. Staying abreast of regulatory changes is crucial for compliance and success.

Example: Analyze how recent changes in FDA&#;s biosimilar policy might impact your biosimilar development pathway. Adjust your strategy to align with new comparative analytical assessment guidelines or post-approval requirements.

3. How Robust is Our Data Analytics Approach?

Review the effectiveness of your predictive modeling in drug development data generation. Have these tools provided the expected level of insight and accuracy in clinical outcomes?

Example: Evaluate the data integration from your CMC activities. How effectively does your data analytics system consolidate manufacturing process data, stability data, and quality control results to predict batch success and compliance?

4. Are We Prepared for FDA Interactions?

Reflect on your last FDA or EMA milestone meeting. Were you adequately prepared, and did the meeting positively influence your program&#;s trajectory?

Example: Assess your readiness for a Pre-Approval Inspection (PAI) by the FDA. Have you conducted mock inspections to ensure your manufacturing sites and CMC documentation align with regulatory expectations?

5. Have We Conducted Comprehensive Gap Assessments?

Analyze your biologic's analytical development process. Are there gaps in your method validation that could impact efficacy or safety assessments?

Example: Review your control strategy for a new biologic. Are there gaps in your understanding of critical quality attributes (CQAs) and their impact on drug safety and efficacy?

6. Is Our Risk Management Strategy Up to Date?

Re-evaluate the risk management plan for your biosimilar&#;s development. Has the emergence of new technologies or market competitors introduced risks that weren't previously considered?

Example: Consider the implications of recent supply chain disruptions on your raw material sourcing strategy. Have you identified alternative suppliers or developed risk mitigation plans for key ingredients?

7. How Effective is Our Quality Assurance Compliance?

Look at the results of your recent internal audit or due diligence. Did it reveal any areas where your manufacturing process could be at risk of non-compliance with FDA quality standards?

Example: Reflect on your deviation management process. Are there recurring issues in production that might indicate systemic problems in your QA/QC processes or a need for more robust training protocols?

8. Are We Utilizing Cutting-Edge Development Practices?

Assess if your approach to formulation development aligns with the latest industry practices, such as using advanced bioinformatics tools for drug design.

Example: Investigate whether adopting continuous manufacturing processes could enhance your production efficiency and quality control, especially for complex formulations like nanoemulsions or liposomal drugs.

9. How Strong is Our CMC Development?

Review the stability data of your small molecule drug. Does it indicate the need for adjustments in formulation or storage conditions to enhance product stability?

Example: Analyze the robustness of your analytical method validation for a new monoclonal antibody. Are your methods sensitive and specific enough to detect variants and impurities that could impact drug performance?

10. What are Our Goals for the Coming Year?

Set specific goals, like initiating Phase II trials for your new therapeutic antibody, ensuring that your objectives are aligned with your overall business strategy and market demands.

Example: Plan for the scale-up of your manufacturing process in anticipation of a successful Phase II trial. Set goals for process optimization, scale-up activities, and preparation for larger-scale clinical or commercial manufacturing.

Incorporating these examples into your year-end review can provide a comprehensive understanding of where your biotech stands and what strategic steps are necessary for continued success in the upcoming year. Remember, in the dynamic biotech industry, a proactive and informed approach is key to navigating regulatory landscapes and technological advancements.

In summary, these ten questions provide a framework for small and emerging biotechs to critically assess their drug development programs at year-end. By thoroughly evaluating each aspect &#; from regulatory compliance to technological advancements &#; you can ensure that your program is well-positioned for success in the upcoming year. Remember, the biotech industry is dynamic, and agility in response to new challenges and opportunities is key to sustained growth and innovation.

As we gear up to bid farewell to this year, it's time to pause and ponder - is your biotech venture truly reaching its zenith? In the whirlwind of research and development, it's easy to lose sight of the bigger picture. But fear not! We've distilled the essence of strategic introspection into an unmissable guide.

The economic crisis is affecting many industries, but what about drug discovery? Are executives changing their strategies because of the crisis? What are some of the trends to look out for? Sarin Kouyoumdjian-Gurunlian of marcus evans talks to seven industry senior executives attending the marcus evans Discovery Summit in Monte-Carlo (Monaco) this March for their strategies and outlook on drug discovery today.

What are the biggest issues facing drug discovery today?

Biondi: The biggest issue facing drug discovery is the barrier to entry that health authorities are constantly raising (most of the time for good reasons) because of the increasing requirements for quality, safety and clinical evidence of efficacy. If companies were receiving approval for 25 new chemical entities per year 5 years ago, but are only getting 20 now, it&#;s not that they&#;re less productive; the barrier is higher.

Pevarello: For big companies, the most prominent issue is meeting the market expectations of sustained high annual growth. For R&D divisions, this means churning out multiple compounds each year that will generate enough revenue to offset products with expiring patents. The main scientific difficulty is predicting which targets are likely to be important in a certain disease. I believe an early preclinical target validation still has a long way to come. All too often a target is fully validated only after expensive clinical trials are performed. The point is that we need an early forecast — at the preclinical level — if a target will be relevant for a certain disease without waiting for Phase II/III clinical trial results. A second problem is the inability to manage a complex and risky process (e.g., drug discovery) in a large, centralized, multinational organization.

Cluzel: Most Big Pharma companies were built to deliver therapeutic benefits based on small molecules that would profit a large community, but that model is changing for two main reasons; first, many of the primary needs are already fulfilled; and second, there is increasing emphasis on safety. If you deliver a drug for many people, you have to strike a balance between side effects and benefit. This balance is now moving towards increased safety. and there&#;s also pressure from the payers, who are more reluctant to reimburse without clear outcome studies. The fact that we are moving from a relative risk reduction to an absolute risk reduction evaluation illustrates this.

Left: Paolo Pevarello is Preclinical Research Director at Newron Pharmaceuticals (Italy).

Right: Giuseppe Biondi is R&D Director at Angelini (Italy).

What are the top priorities for drug discovery companies at the moment?

Mikkelsen: The priority is to do more ex vivo analysis on humans earlier in the drug discovery process.

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Roesner: Identifying and developing safe and effective new drugs for areas of high medical need.

Engel: Cash management — to still be alive in the next 1 or 2 years. Companies are trying to do this through building partnerships and alliances, and selecting the most promising projects to focus all capacity on.

What is the most critical stage in drug discovery?

Soehngen: One issue with drug discovery is wrong expectations. Frequently, people try to achieve the &#;wonder drug&#;, which is not achievable, and then they stop midway. I think this has a lot to do with making wrong &#;or right, go&#; and &#;no go&#; decisions.

Mikkelsen: The most critical stage is the translational process when you take the drug from animals to humans. It works on animals then it doesn&#;t work on humans, and then the drug will fail.

Cluzel: The choice of the target at the initial stage (initiation of the target) is crucial &#; you also need a little bit of luck. After that, it&#;s proof of concept in humans, which is also important. If you are going for sub-group therapy, you need to ensure you have correctly identified correct the sub-population in humans.

Biondi: It's difficult so say which is the most critical stage. The most risky is certainly the clinical trial stage because it&#;s the most expensive. I&#;m not expecting drug discovery companies to make the effort to discover new drugs and new targets; this usually comes from academia and unless you&#;re a huge company you don&#;t even consider discovering a new target. The selection of the first indication, planning of clinical trial and clinical development are usually very important. If you don&#;t have a well-designed clinical programme, if you&#;re not very self-disciplined, and if you&#;re surrendering to pressure from the CEO and board of directors to speed up without properly doing all the work, then you risk what we have seen recently: more failures in Phase III. This means you are failing at the point when you have spent almost 80% of the total cost of development, including discovery.

Pevarello: Personally, I believe the ability to turn a good preclinical compound into a successful drug is the most unmet need. This problem stems from preclinical animal models that are not sufficiently able to predict activity and toxicity in the clinic (in particular for the central nervous system and oncology). Working for years on a target that proves to be irrelevant or wrong (efficacy, druggability or toxicity) is a real disaster for the industry.

Roesner: For me as a chemist, the most critical phase is during chemical optimization — starting from a good lead to the identification of a development candidate. It has to be as short and efficient as possible, and incorporate all available technologies including predictive methods for early absorption, distribution, metabolism, excretion and toxicity.

Left: Marc Cluzel is SVP of R&D at sanofi aventis (France).
Right: Manfred Roesner, R&D scientific coordinator and functional interfaces at sanofi aventis Deutschland GmbH (Germany).

Not shown: Jens Mikkelsen is Scientific Director at NeuroSearch (Denmark).

Why is there such strong focus on biologics?

Roesner: Biologics are mainly being considered in difficult and high need areas. In theory, they have the potential to tackle some targets more precisely, but they still have to meet high-safety standards. They can mainly be considered for severe diseases where in vitro application is acceptable.

Biondi: Biologics is a logical trend because biologics, particularly the basics of biologics, is 'replacing therapy'. I say replacing because in many cases the 'therapeutic proteins' you&#;re giving to the patient are something that his organism does not produce, or does not produce in adequate amount of. To put it another way, you are just increasing something that already exists in your body, a completely different approach from introducing a synthetic small molecule.

The concept of 'replacement' obviously does not apply to mAbs, nor to the more recent approaches/technologies, such as iRNA. mAbs have the great advantage of immunological specificity and there is a growing number of examples where the use of mAbs allowed the proof of concept or the first validation for new pharmacological targets. Moreover, they have already provided — with several products already approved and in use — good evidence of the efficacy of this approach. The disadvantage of producing biologics is that it&#;s very expensive compared with producing small molecules. The other disadvantage is that you can rarely administer biologics orally; they usually have to be delivered intravenously.More recent 'biologics' such as iRNAs are very good promises but still have to provide good reliable evidence in practice.

Engel: The focus is on RNA-based therapies, vaccine development, antibody-drug conjugates, gene therapy and so on. Biologics is the way forward; it may be able to treat unmet medical needs, is more selective and may have fewer off-target effects. However, the disadvantage is that, currently, the balance between science and business is still wrong in the amazing area of biologics, which means the biotechnology industry as a lot of interesting projects in early preclinical stage without a chance to find a partner and to finance the development costs. A major issue is the step from bench to bedside and proof of concept in the clinic. In some of the new technology areas, the intellectual property landscape is also complicated.

Mikkelsen: There is a strong focus on biologicals because they have high affinity and efficacy, but it&#;s not an easy way forward in CNS because you can&#;t get the biologicals into the brain.

Should drug discovery companies change their strategies because of the economical crisis?

Cluzel: We, Sanofi-aventis need to change strategy, but not because of the economic crisis; it should be done on a fundamental basis. The classic model of the 'collective medicine' is no longer valid for most of the diseases for which there is already some primary care; for example, it is very difficult to introduce a new product for hypertension because there are so many products available that are both cheap and efficient.

Have you altered the way you work to accommodate the new economic landscape?

Pevarello: Yes, of course. We feel the crisis almost on real time. When the stock plunges, the drug discovery budget shrinks. Also, we are much more careful than we have been in the past with outsourcing opportunities. We tend to be more selective when it comes to buying external services and we select only those activities that are considered absolutely essential for a project's progression.

Engel: Yes. The company is now concentrating on the late-stage projects rather than starting new drug discovery programmes; for example, clinical development of our cytotoxic conjugate AEZS-108 versus a new vaccine project where we have good patent protection, but are still in preclinical development.

Left: Juergen Engel is President & CEO at Æterna Zentaris (Germany).

Right: Wolfgang Soehngen is CEO at PAION AG (Germany).

What trends are emerging now?

Biondi: I would say what&#;s emerging now is more rational drug design or discovery. Genomics is certainly coming to fruition and, to some extent, we are also bringing personalized medicine to fruition, which means the use of drugs in the future will be based on the single patient or, at least, sub-groups of a patient'ss situation. This means that as you&#;re developing new drugs based on better defined and validated targets, in the future you will be able to use the drug that better fits the situation of the single patient in terms, not only of efficacy, but also of tolerability. This means also your ability to use the genomic screening of the patient for the selection of the drug you're going to prescribe to him. These drugs will be for smaller markets, but the efficacy will be higher because the ratio between benefit and risk will be more favourable. Governments will most probably be willing to pay more — perhaps for fewer patients, but those patients will receive more benefits.

At the other side of the range, do we want to consider 'cell therapy' as a part of biologics? I am sure the category will appear reductive to some of the specialists working on this field. In my opinion, the semantic or classification can wait opinion at least until we have good clinical evidence for Cell Therapy (which I hope will be soon).

Mikkelsen: I think the trend is in clinical trials and trying to identify the right patients for the right treatment; the procedures are going to be better-defined based on genomics and biomarkers. I think that's really going to change our view on how the drug discovery process is going to focus on sub-indication or smaller therapeutic areas. We can then identify groups of patients that suffer from one disease, which is characterized by certain biomarkers, and treat the specifically.

Cluzel: The drug discovery industry is moving towards characterization of the disease based on biochemical process for an individual or a sub-group of individuals rather than symptoms, which change discovery a little because identification of the biochemical or biomolecular detrimental process in humans may happen first. A second trend that is growing fast is representative medicine. You also have vaccines against noninfectious diseases, nanotechnics and the technical delivery of RNA. A second trend that is growing fast is regenerative medicine. You also have vaccines against noninfectious diseases, nanotechnics and the delivery of RNA.

Soehngen: One of the biggest trends I&#;m seeing right now is the repositioning of existing drugs. Although they might not be chemically new, their application is new and that is as justifiable as creating something from scratch. This probably has a lot to do with another theme in the industry, which is essentially to de-risk. De-risking is a prominent theme these days and I think repositioning drugs that have an established safety profile and using them in a different indication meets those criteria fairly well and using them in a different indication that meets that sentiment fairly well.

Pevarello: Observing how the industry is evolving, I see a comeback to early, intelligent in vivo testing in the preclinical setting, having realized that &#;predictive&#; in vitro (not to mention in silico) methods are not so predictive. The challenge is, how to make in vivo testing more &#;intelligent&#; and, at the same time, reduce the number of experiments and maximize the knowledge we extract from them.

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