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Bridging the Gap: Overcoming Bottlenecks in the Development of Therapeutics for Infectious Diseases - Workshop Summary Report

National Institute of Allergy and Infectious Diseases
National Institutes of Health
August 9-10, 2012

Introduction

On August 9-10, 2012, the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, held a workshop to identify and discuss impediments that may slow or prevent development of therapeutics for infectious diseases. The organizers brought together product development experts from industry, government, academia and the non-profit sector to interact with NIAID-funded researchers and government stakeholders. The goals were to identify and clarify problems that exist, to brainstorm about ways to address them, and to educate NIAID investigators and their Federal partners about this important issue. Approximately 140 people attended the workshop, which consisted of presentations, discussions, and breakout sessions about specific areas of concern. A videocast of the first day’s sessions is available, and slides from the presentations may be obtained by contacting Dr. Jane Knisely. The Workshop Agenda is available on the NIAID website. This report is organized according to the Workshop format and summarizes the speakers’ and participants’ presentations and ideas.

Overview of the Problem

The need for new antimicrobials is greater than ever, but many bottlenecks impede antimicrobial product development. These bottlenecks occur throughout the drug development pathway. Some have a scientific basis, while others derive from business and financial concerns. In recent years, the pace of drug discovery and innovation has slowed. For example, all currently marketed antibacterial drug classes were discovered before 1987, although some newer drug classes are currently in clinical trials. While antimicrobial resistance receives much attention and, for some pathogens has reached a critical point, resistance is only part of the problem. Treatment of drug-sensitive pathogens may still fail due to individual patient differences.

While biopharmaceuticals for infectious diseases is a fairly new area with great promise, it faces have many of the same challenges as small molecule development as well as some additional ones. In general, development of antimicrobials for use in special populations such as children, and pregnant or lactating women, is particularly challenging. In this summary report we will discuss the major themes of the workshop, the bottlenecks identified, and present some possible opportunities and resources.

Bottlenecks in Early Stages of Product Development

Product development begins with research and discovery, where novel ideas and concepts can be explored. Several bottlenecks that may hamper the early stages of product development were discussed, including the quality and quantity of targets. Up until now, a relatively small number of targets have been under consideration as multiple antibacterial screening methods have identified the same relatively small group of targets. New ideas to be considered when developing targets include bacterial uptake and efflux systems and drugs with low resistance potential. Gram-negative bacteria and viruses represent unique challenges related to targets. New approaches using modern technologies are needed to expand the range of targets, and better ways are needed to determine which targets are likely to be “druggable.”

Another significant issue is that a broader scope of chemical entities is needed for screening activities. Many participants highlighted problems with current chemical libraries, noting that they may be “mined-out.” Antimicrobials are different from other classes of drugs chemically, and libraries need to reflect this. The right screening libraries for antimicrobials are different from those for mammalian targets. Using modern approaches to look at natural products was suggested. While natural products may not directly yield new drugs, they might offer new scaffolds for chemists to explore. Moving towards combination treatments, either using more than one antimicrobial or using an antimicrobial plus another therapeutic to increase effectiveness, may offer one solution for combating resistance. New drugs may be found that, when combined with licensed drugs, can expand clinical activity and not only overcome resistance but even prevent it from developing.

Once targets have been identified and libraries screened, it is important to understand the difference between “hits” and “leads.” Hits are compounds that display the desired activity while leads display more potent and selective action and have properties that are favorable for development into drugs. Leads are usually selected after a more refined evaluation of hits. Lead candidate selection must be based on solid science; it is also important to validate drug mechanisms inside cells. A decision tree to guide project progress and triage/selection of lead compounds is essential.

Participants also highlighted the importance of medicinal chemistry in early drug development, and the need to integrate chemistry and biology. Computational and structural biology need to be included as well. Successful drug development requires multidisciplinary teams with the right expertise, good communications, and a common vision.

It was suggested that early stage product development activities begin with the end in mind: identifying an unmet medical need and a strategy to satisfy it is critical. It is important to clearly define the desired product characteristics at the beginning of a drug development project. A simple product profile should be developed early on. This increases the likelihood of success and makes the best use of resources.

Bottlenecks in Preclinical Development

Once a target and early drug candidates with data on possible mechanisms have been identified, IND-enabling, pre-clinical studies can begin. Different bottlenecks may then come into play; several were discussed at the workshop.

While minimum in vitro inhibitory concentration (MIC) is an important characteristic, it does not necessarily reflect effectiveness in vivo. Reducing drug clearance and having an acceptable therapeutic index are as important as a low MIC. In addition, the spectrum of activity needs to be considered. The decision as to whether to pursue broad or limited spectrum will vary from project to project. While a low therapeutic index in lab studies is generally considered a problem, it may actually be acceptable in real life settings. Thus, while low potency molecules are often dropped, in fact, they may have potential for success in a clinical setting.

A major impediment that still exists for many infectious diseases is the lack of suitable animal models for testing pre-clinical efficacy. This is particularly true for viral diseases and tropical diseases, where pathogenesis may be specific to host species. Factors that contribute to this problem include lack of sufficient data about the natural history and pathology of the human disease that would provide guidance for development of the animal models. Conducting animal efficacy studies too early or with inadequate models can be a source of project failures. Other pre-clinical data is needed first. Use of humanized animal models is a new approach that has promise and should be explored.

Pharmacokinetic (PK) and pharmacodynamic (PD) studies provide critical pre-clinical data. Recently there have been huge advances in these fields as well as toxicity evaluation and pharmacometric methods. Modern approaches should be adopted and used early to increase the likelihood of success. Simple, early PK/PD studies done before animal efficacy studies can prevent unnecessary project failures. Problems related to Adsorption, Distribution, Metabolism and Excretion (ADME) are best identified early. In spite of recent advances, better ways to assess safety and predict toxicity would be a welcome addition. Methods that would take into account differences in metabolism across species or for evaluating drugs with host targets are current gaps. More sophisticated PK/PD studies later in pre-clinical development may guide the design of appropriate clinical studies. Good PK/PD data can be the basis for deriving an appropriate human dose and for obtaining approval under the animal rule. In some cases, however, PK/PD data from animal studies may not correlate with that from humans, and missed opportunities for drugs that might have been safe and effective in humans can result. Interpretation of toxicity data should take into account the intended use and duration of treatment for the drug.

Optimizing drug candidates to have the right properties for ADME as well as desirable features to interact with the target and avoid resistance mechanisms is a difficult process involving multiple components. If structure-activity relationship (SAR) doesn’t improve with new molecular variations, the project is unlikely to succeed. Optimization is largely empirical now, and would benefit from more systematic approaches that integrate medicinal chemistry and biology. Complex regulatory requirements relating to pre-clinical data are an important part of the development process, and can sometimes be a bottleneck in getting to clinical studies.

Bottlenecks in Chemistry, Manufacturing and Controls Development

Chemistry, manufacturing, and controls (CMC) encompass many complex activities including making active drug ingredient, developing an appropriate formulation, and testing with well-developed analytical methods to prove identity, strength, quality, and purity. CMC activities should take place in parallel with other product development activities. Manufacturing sufficient material to support large clinical trials and post-approval marketing can be a big hurdle with respect to both quality and quantity; scale-up feasibility should be addressed in the early stages of product development. Producing pilot lots can be a serious bottleneck for some products, particularly biologics. Raw materials availability, chemical process suitability for scale-up, and availability of facilities have the potential to be bottlenecks that can be avoided with good early planning.

GMP considerations are a critical aspect of CMC and product development in general, and must be considered from the beginning. For biologics in particular, keeping complete written records is essential as are records management, traceability and chain of custody. Avoiding animal-derived materials is desirable. Building quality systems and establishing assays and standards for stability, potency, and release are crucial throughout the whole project. Quality issues must be addressed to avoid costly mistakes and expensive repeats.

Bottlenecks in Clinical and Regulatory Development

Once an IND has been obtained, crucial studies in humans can commence. Conducting clinical trials and obtaining regulatory approvals are intimately related issues. Clinical trials are inherently complex and are influenced by all earlier stages of product development. Mistakes and omissions early in development can have major consequences during clinical trials.

Current standards and processes for clinical trials have evolved over time to maintain scientific rigor and incorporate essential safeguards. Because of the complexity of the clinical trials process, significant delays can result at several points. Factors that affect the success of performing clinical trials in the fastest and safest manner may include: writing protocols that involve a large numbers of stakeholders; obtaining approvals from a variety of institutional and governmental officials; developing multi-party clinical trial agreements (CTAs); enrolling subjects that represent special populations such as women, children, and the immune-compromised; attaining sufficient patient enrollment due to stringent entry criteria and exclusion of prior antibiotic use in patients; legal and ethical issues with regard to enrolling very sick people; use of concomitant drugs by some patients; and demonstrating statistical significance for trials designed to show resistance suppression by combinations of drugs. The current standard of non-inferiority clinical trial designs (intended to show that the effect of a new treatment is not worse than that of an active control by more than a specified margin) leads to difficulties reaching clinical endpoints. There is a great need for better clinical trial designs, better ways to define sub-groups, better ways to enroll patients in trials, and better outcome measures, particularly for less serious diseases. Historically, controlled trials can be a way to solve the non-inferiority issue with no comparison group. Some of the current paradigms for need to be reassessed to facilitate designing achievable clinical trials, and FDA is actively working to develop and update clinical trial guidance documents to help drug developers attain this goal. In addition, the need for compassionate use must be balanced with rigorous standards for scientific data.

The importance of companion diagnostics as integral parts of clinical trial protocols was also discussed by meeting participants. The expense of clinical trials is another challenge that was brought out as a significant hurdle to advancing new drugs.

With regard to regulatory issues, a constructive relationship with FDA is essential throughout the product development process for both small molecules and biologics. The regulatory path for many biologics is still being determined. Successfully anticipating and meeting regulatory requirements is essential for moving products forward in a timely manner. Meeting participants mentioned the Limited Population Antibacterial Drug (LPAD) approval mechanism as a possible alternative approval pathway for antibacterial drugs in cases of unmet medical needs.

Bottlenecks in Business and Financial Aspects of Product Development

Many therapeutics fail to reach licensure because of business and financial bottlenecks, not problems related to science. Several aspects of this dilemma were discussed at the workshop.

Lack of sufficient financing at all stages of product development is usually a bottleneck. Without sufficient, continuous funding, even promising projects may fail to reach completion. Small companies and academic investigators often must cope with uncertain funding that lacks long-term continuity and takes a long time to secure. In particular, obtaining funds from government sources takes time, and the process can be complex. In addition, there may be tension within companies between ending projects early to save resources and avoiding missed opportunities. Drug pricing is another important consideration in product development since market potential is traditionally the strongest driver for pursuing a drug development project.

Small companies and academics often wish to enter into arrangements with larger pharmaceutical companies. These agreements can be difficult to work out, and may ultimately depend on the risk-benefit equation for the larger partner. In addition to financial risk, companies consider risks relating to obtaining regulatory approvals, clarity of intellectual property, suitability of manufacturing at large scale, clear data on safety and efficacy, and overall corporate strategies regarding the expected market. The equation changes as product development proceeds, risks decrease, and value increases. The most successful arrangements often occur during early clinical trials. Negotiating agreements is time-consuming and complicated. If experienced, in-house expertise is not available, employing outside consultants may lead to more advantageous outcomes. Financial issues can be particularly challenging in developing drugs for special populations, tropical diseases and orphan diseases because of perceived limited market value.

Having a new development path for an unmet need plays a significant role in successful negotiations. Small companies need to understand the market for their product and not exaggerate market opportunity. A good market assessment can be costly, but is usually worth the expense.

Education for Product Development

As was emphasized throughout the workshop, infectious disease drug development is very complex and requires the integrated activities of many people with different experience and expertise. While bottlenecks cannot be eliminated entirely, better training opportunities and more effective ways to learn from others’ past experiences would help academic investigators and small companies. Concerted efforts to facilitate structured learning opportunities would promote faster and easier drug development activities in academia, and, more specifically, enable chemists and biologists to work together more effectively. There is a great need for mechanisms to share the lessons of the past so that those new to product development do not repeat mistakes and “rediscover the wheel.” Industry can make significant contributions in this area. Industry “internships” is one mechanism that might help.

Efforts to make the drug development process less empirical and based more on underlying principles are needed. Evidence-based practice should be incorporated into the drug development process more frequently and consistently. There is a need for more systematic approaches based on careful planning and execution. More can be learned from other drug development areas (non-antimicrobials). There is a need for more “out-of-the-box” thinking about the best ways to face the challenges of drug development, since the outcomes are so important.

Resources and Opportunities

There are resources and opportunities that can provide help-- fiscal, scientific and otherwise. Having a variety of partnerships among government, universities, industry, and others is one of the most important messages of the workshop. Collaboration between academia and industry, biologists and chemists, and all of those with an interest in infectious disease drug development should be improved and promoted. Gaps in expertise can be overcome by forming collaborations, with close interactions between all parties being important. Partnerships with NIH can offer funding opportunities and access to product development resources.

Outsourcing was discussed as a way to obtain valuable expertise not available in house. Chemistry may be easier to outsource than biology or early development, and all outsourcing requires careful oversight and direct involvement of company personnel, sometimes on-site at the contractor’s facility. Outsourcing works best when all partners’ goals are aligned, and a clear decision-making structure needs to be in place from the beginning. The company needs enough independent expertise (internal or from consultants) to oversee contractors adequately. In order to have a successful long term outcome, quality must take precedence over cost.

A panel of federal and other experts discussed their resources that may be available to help with product development. For more information go to agency websites or contact workshop speakers.

  • Visit the NIAID website and contact the relevant DMID program officer. For extramural researchers, funding is available through investigator-initiated grants and targeted initiatives. Other resources may be available through contracts that provide gap-filling technologies and tools, pre-clinical development services, and clinical evaluation. Examples of preclinical services include medicinal chemistry, drug synthesis, biopharmaceutical development resources, PK/PD and GLP toxicology, as well as access to in vitro screening and in vivo efficacy models. Therapeutics that have advanced through preclinical development may be eligible for Phase I safety testing through NIAID clinical trials networks.
  • Communicate with the FDA; pre-IND is a key time for discussions. FDA is facilitating efforts to develop drugs for serious and life-threatening infections. For more information:
    • The FDA is promoting innovation through enhanced communication between FDA and sponsors during drug development under the Prescription Drug User Fee Act (PDUFA).
    • Generating Antibiotic Incentives Now (GAIN), part of the Food and Drug Administration Safety and Innovation Act (FDASIA) encourages development of antibacterials and antifungals to treat serious and life-threatening infections.
  • The National Center for Advancing Translational Sciences (NCATS) programs that may provide extramural investigators with resources and services for product development include Therapeutics for Rare and Neglected Diseases (TRND), Bridging Interventional Development Gaps (BriDGs) and Toxicology for the 21st Century (Tox21) For more information, visit the NCATS website.
  • U.S. Department of Defense (DoD) priorities in the area of Chem-Bio include countermeasures (pretreatments and therapeutics) for major threat agents. For contract funding opportunities, see DoD Broad Agency Announcements (BAAs), available through FedBizOps. DoD may also be able to provide services, such as screening and animal models, to small companies and academic researchers.
  • Resources may be available through the Bill & Melinda Gates Foundation discovery programs or through partnerships in specific interest areas (e.g., malaria, tuberculosis, leishmaniasis, trypanosomiasis, onchocerciasis, filariasis, diarrheal diseases, HIV).
  • The mission of the Biomedical Advanced Research and Development Authority (BARDA) includes a focus on broad spectrum antimicrobials. Funding for clinical trials including Phase III is available through BAAs; investigators should first contact BARDA to discuss ideas.
  • Venture capital funding may be available, depending on perceived incentives. But if the financial incentives are not there, such funding is unlikely. Other bottlenecks to obtaining venture capital may include the lack of financial incentives, regulatory challenges, patent issues, and slow return on investment.

Summary

Attention to the following aspects will improve chances of drug development success:

  • Envision a well-differentiated product that will have its own niche and fill an unmet medical need.
  • Establish a strong product development plan to minimize risk.
  • Harness a variety of resources and skills to aid in successful product development.
  • Focus on understanding the biology; incorporate chemistry early.
  • Know how to interpret results and choose appropriate next steps.
  • Think big picture, and get help for areas outside of your own expertise.
  • Work with Federal agencies and others to build a variety of partnerships.
  • Pay careful attention to clinical trial design; consider novel designs.
  • Communicate your lessons learned.

Last Updated June 29, 2013