Optimizing Drug Development Strategies

Exploring methods to improve the process

By Dr. Kenneth Sokoll

The phases of drug development include discovery, preclinical development, clinical development, filing for licensure, approval/licensure and post-approval. Discovery typically includes basic research, drug identification and early-stage process and analytical method development.

Preclinical development includes laboratory and animal studies, where early toxicology and pharmacology studies are conducted in the appropriate animal models. As the preclinical development plan will be used to support the clinical studies, a draft of the proposed clinical protocols should be prepared at this time. All studies relevant to proving the drug and product are safe should be completed. Improvements to manufacturing processes and the analytical characterizations of the drug substance and drug product (yield, purity, stability) are completed in support of the preparation of an investigational new drug application (IND). With regulatory review of the IND and receipt of approval to proceed into clinical trials, the preclinical phase is complete. Clinical development follows four phases:

Phase I: designed to primarily evaluate safety, tolerability and pharmacokinetics;

Phase II: designed for extended safety evaluation, efficacy and pharmacokinetics; and

Phase III: large-scale studies linking efficacy, safety and pharmacokinetics. At the completion of Phase III an application for licensure is submitted to the FDA, employing either a new drug application (NDA) or a biologics license application (BLA). The FDA will evaluate the applications and decide:

• Whether the drug is safe and effective as indicated, while weighing the risks against the benefits;
• If the drug product is labelled correctly;
• If the drug has been characterized adequately to validate the drug’s identity, strength, quality, potency and purity attributes; and
• Whether the drug substance and drug product have been manufactured following current Good Manufacturing Practices (cGMPs.)

Phase IV: designed to track long-term or uncommon side effects, and occur after licensure has been completed. The FDA provides several guidance documents, which can be used as reference in the pre-IND process. Detailed information may be found at www.fda.gov.

A Team Approach

Internally, drug development requires a team approach. Contributions will be made from manufacturing, quality control, quality assurance, preclinical, clinical, regulatory affairs and project management. Key individuals or groups with these skill sets will be found in all large integrated pharmaceutical companies.

In the case of smaller firms, such as Liponex, few individuals have the required experience and, therefore, the company cannot resource the full effort internally. In these instances, it is very important to identify key contractors for manufacturing operations, formulation and compounding, assistance in all aspects of the preparation and organization of the required regulatory documentation, and in conducting clinical trials. When outsourcing key elements of the development program, it is essential to develop an open dialogue and maintain good communication. The manufacturing and clinical groups will require auditing to establish that good laboratory practices (GLP), cGMP and good clinical practices (GCP) are in place and strictly implemented.

Moving from Research into Development

Several factors play a role in determining whether to take a drug from the research stage and into development. Market potential and health benefits are foremost amongst these. In practice, the best policy is to have no more drugs in development than are sustainable, with preference for resources given to those that have the best chance of being first in class and/or first to market. The chance for successful development from a clinical standpoint is another critical parameter to evaluate. Factors of most importance include:

• Identifying drug candidates with poor physicochemical properties, such as poor aqueous solubility and/or poor dissolution characteristics.
• Identifying poorly adsorbed or metabolized compounds with suboptimal pharmokinetics and/or toxicological properties.

Hydrophobic drugs are examples of molecules that exhibit several of these problems. Physicochemical parameters such as solubility, lipophilicity and stability should be evaluated in any early development program, providing drug molecules with the most preferred physicochemical properties for formulation and dosage form development.

With respect to issues related to toxicological problems, gene transcriptional profiling has the potential to predict drug candidate toxicity and with the development of transgenic and knockout animal models, preclinical toxicogenomic studies are greatly aided. Although these emerging technologies provide good opportunities to shorten drug development timelines, it is important to note that there remain quantitative and qualitative differences in dose responses and sensitivities between animal models and man.

Companies normally complete preclinical screening assessments from which a few leading candidates can be identified. The task is then to provide full specifications for the selected drug and drug formulation, combining this with evidence and reasoning for safety and efficacy, and then move into clinical trials after meeting the requirements of the governing regulatory authority. Companies entering Phase I trials will always be concurrently engaged in development of the drug product formulations as the primary purpose for Phase I trials is safety and not efficacy.

There are alternative strategies that seek shortcuts in the regulatory pathways, such as re-profiling marketed drugs for alternative indications. With this approach, costs are lowered and risks minimized as often many of the more costly and time-consuming regulatory requirements have already been identified and completed. Several famous drugs were found to have their greatest therapeutic potential in other unanticipated indications in this way. Examples include Viagra (erectile dysfunction), Evista (osteoporosis) and Hytrin (benign prostatic hyperplasia). Furthermore, subsequent to approval, nearly 90% of marketed drugs find important new clinical indications.

Managing the pipeline as R&D continues with multiple candidates is an ongoing proposition. Typically, if and when a company has made what it considers to be a significant advance in drug development, it is the responsibility of management to make every effort to bring that advance into the current clinical development timeline. One of the advantages of small companies is that they have the flexibility to make these kinds of changes and quickly redirect resources.

The Role of Emerging Drug Development Companies

The internal approach of large pharmaceutical companies has become one where several compounds are evaluated early in the discovery process for drug-like physicochemical properties, often with the assistance of high-throughput screening methods to nominate lead candidates for subsequent pharmacological and toxicological evaluations. This process has been adopted to ensure timelines are not extended due to poor physicochemical properties of drug candidates and this ultimately reduces the overall cost of developing drugs. The cost of taking one compound through full development and clinical trials successfully is typically quoted as $800 million or more. It is important to keep in mind that only about one third of those that are commercialized and eventually reach the market are ever profitable. A recent report entitled “Estimating The Cost Of New Drug Development: Is it really $802 Million?” appeared in the March/April issue of Health Affairs and was prepared by Christopher Adams and Van Brantner, both employees of the Federal Trade Commission (FTC). This detailed study on the cost of prescription drug development sampled information from over 3,000 compounds and public databases and arrived at a slightly higher figure of $868 million, of which the preclinical component amounted to $381 million and the clinical component amounted to $487 million. The results of this study illustrate the importance of having a well-developed regulatory strategy in place during the early phases of drug development to ensure that costs are minimized.

Notable exceptions to these estimates in the U.S. include those drugs that qualify for fast-tracking of human clinical trials and registration approvals due to the life-threatening nature of the disease (such as AIDS drugs). Currently, there are few drugs in mid- or late-stage clinical trials that can be described as blockbusters capable of generating annual revenues in the range of billions of U.S. dollars.

Given these financial realities, internal development along several paths is unsustainable. Consequently, large pharmaceutical companies are always actively searching for small companies with attractive technology to offer. In-licensing of advanced drug candidates has grown more competitive as companies race to diversify their internal development pipeline. This has the benefit of reducing risk and having additional products closer to market.

Small drug companies are commonly spun out of academic incubators where the discovery of new drug targets has been the primary focus. Firms with the best opportunities will have solid drug candidates conceived through sound scientific research; a well-developed intellectual property portfolio; and a drug development plan designed with regulatory compliance in mind to successfully advance the drug candidate through early clinical trials. Companies with this kind of profile fulfill an important lead role in supplying a pipeline of new drug candidates for major drug companies to develop toward full commercialization.

This approach may be considered streamlined but presents several challenges. The two most common impediments to effective drug development today are bioavailability and toxicity. Small companies rarely have the full expertise and cash resources needed to execute these very expensive studies, which can easily range into the millions of dollars and require several years to complete. Consequently, it is important that small firms engage regulatory authorities early in the development process and seek guidance from a diverse group of opinion leaders.

Drug Development Planning for a Worldwide Market

The successful completion of an Investigational New Drug application (IND), the first milestone a company reaches prior to initiating Phase I clinical trials, requires a logical development plan. After completion of several trials, an NDA or BLA may be filed and drug registration may follow. Adherence to FDA/ICH guidelines and the implementation of GLP, cGMP and GCP are essential ingredients to achieving drug development goals.

Depending on the target indication and the type of drug, its classification and the intended market, the least burdensome regulatory pathway should be sought, with the caveat that no compromises on drug product safety and effectiveness are made.

Chief among the factors that determine the approach an emerging company will take to drug development lies in the company’s understanding the regulatory path required to commercialize the drug, which can vary, depending on whether the drug is intended for U.S.-only or multinational development. Fortunately for Phase I and II clinical trials, the format of an IND developed in the U.S. can be used as a template for applications in Europe. However, several differences between the U.S., Europe and Japan with respect to requirements of toxicity and pharmacokinetics may be expected. On the local level, specific processes do differ and there are few preventative measures one can take to anticipate how local authorities may react in comparison with the equivalent U.S. regulatory authority. To mitigate that risk, companies can look to opinion leaders and consultants to weigh risk vs. benefits. In the U.S. and other jurisdictions, assistance is provided in the form of written guidances. However, guidances may be waived and interpretations vary. Consequently, it is important to seek external guidance from advisors and establish a dialogue with the regulatory authorities early in the development process.

The Importance of Optimized Drug Development Strategies

The goal of every early-stage drug company should be to reach human clinical trials as expeditiously as possible and validate the drug product in the model that matters most: human subjects. Drugs that have successfully advanced to the IND stage and received regulatory review are more highly valued in the eyes of investors than those in earlier stages of development. Accordingly, it is imperative that early-stage drug companies place a high priority on conceiving and executing a logical drug development plan. A properly designed and implemented drug development strategy should ensure that the FDA’s most commonly cited reasons for problems with INDs are dealt with before they can cause milestones to be missed, seriously delaying the drug development timeline. These common pitfalls include:

• incomplete or inadequate chemistry, manufacturing and controls (CMCs);
• poor or non-existent validation;
• inadequate stability and testing specifications;
• insufficient preclinical support;
• poor clinical trial designs and
• non-compliance issues related to clinical practices.

A properly managed drug development program will meet the standards for quality expected by large firms performing due diligence at the appropriate stage of a business development deal. Through this process, the large company is looking to place a value on any new drug product acquisition. A well-executed plan will also facilitate the technology-transfer process, which is often a weakness in smaller firms.

By contrast, poorly managed programs often stem from the dilution of resources in R&D, funding and manpower. Forecasting program needs is a skill that links the efforts of all senior management. Inattention to detail in this area can lead to the failure of more than one promising drug candidate in a company’s pipeline and company valuations can be limited by poor forecasting.

Common Challenges for Emerging Companies

Drug development is a clearly defined process that moves forward in defined stages. The key to success can be directly traced to achieving development and clinical milestones.

Senior management in emerging companies must be unafraid to cut projects that are not progressing and dilute the overall development effort. For public companies trimming the pipeline requires careful considerations since it can adversely affect stock price. In truth, shareholders are best served by knowing that the most advanced drug candidates with the greatest chance for clinical success are receiving the most attention.

One of the great challenges for all small companies actively developing drugs today lies in creating a culture of commitment to quality throughout the organization. For current thinking of quality initiatives the reader is referred to new ICH guidelines Q8: Pharmaceutical Development, Q9: Risk Management and Q10: Quality Systems, and their potential impact on manufacture control of active pharmaceutical ingredients.

Members of senior management with pharmaceutical experience should be capable of instilling a sense of urgency while maintaining high levels of productivity. In particular those with a firm knowledge of CMC, toxicology and regulatory affairs will be in a position to play a lead role and mentor junior staff during the transition from discovery to development.

In my opinion, emerging companies that review their pipeline objectively and strike a balance between properly resourcing and developing their lead candidates in the clinic while nurturing their next generation of drug candidates will have the best chance for success and sustainability.

Dr. Kenneth Sokoll is vice president of drug development at Liponex, Inc. He has 12 years of experience in the field of pharmaceutical and vaccine development, quality control, quality assurance, manufacturing and regulatory affairs.