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SCIENCE & TECHNOLOGY Maximizing the Value of Early Phase Drug Development By Cecil Nick, BSc, FTOPRA and John Lambert MD, PhD In the current environment of increasingly rigorous regulatory requirements and tightening fiscal constraints, it is more critical than ever for sponsors to optimize selection of new drug candidates and develop them effectively. Early phase clinical studies provide pivotal decision points that support selection of the right candidate and the right dose to maximize success during the dollar-hungry Phase 3 program. A mistake in early phase development could escalate to a costly failure of the Phase 3 program. According to current estimates, over 55% of drugs fail while in Phase 2 and over 36% fail while in Phase 3 development. In many cases, the reasons for failure are underinvestment in the early phase program or premature entry into Phase 3 to meet market expectations. Either can result in insufficient data to design and successfully conduct the Phase 3 program. This article explores ways of accelerating the completion and maximizing the value of the early phase clinical development of new medicines, rapidly providing informative data to drive informed decision making in the design and conduct of the Phase 3 program. Preclinical to Phase 1 Drug development starts with Phase 1 and, in effect, the success of the whole program pivots 38 March 2011 on a well-thought-out and well-executed group of studies. These studies will provide critical information on safety, pharmacokinetics (PK) and pharmacodynamics (PD) and often proof of mechanism for appropriate design of the subsequent Phase 2 trials. These exploratory studies, along with drug interaction, ethnicity, elderly, gender and translational studies, provide detailed information about the drug necessary to progress the development program. Because preclinical work will never be 100% predictive of a drug’s effects, safety is always the first objective in early human trials. These should proceed cautiously. Many drug safety issues that arise at later stages of clinical development could have been anticipated with better analysis of safety signals from data in earlier trials. An example is the cardiac QT ECG changes occurring with prokinetic agents being developed to improve gastric emptying; more-intensive review of cardiac safety data may have revealed these changes earlier. Typically, the initial clinical dose of a new drug is based upon the results of acute and 14-day animal data with a 10- to 100-fold safety margin over the no effect level (NOAEL) in the most sensitive and relevant animal species. The exact safety margin will depend upon the expected therapeutic window and potential risk to the trial subjects. Generating interpretable preclinical data can present a challenge, particularly when working with some biological products. An example is a protein that shows no or limited pharmacological activity in animal species or is rapidly neutralized or cleared due to early generation of anti-drug antibodies in animals. Thus, it may not always be possible to conduct the generally expected preclinical program before moving into the clinic. In these situations, greater caution will be needed in Phase 1, i.e., starting with very low doses in a limited number of trial subjects. Animal doses need to be converted to human equivalent doses to accommodate differences in body surface area; for example, NOAEL is divided by 12.3 for a mouse, 6.2 for a rat, 1.8 for a dog and 3.1 for a cynomolgus or rhesus monkey. However, for biologics, the introduction of an arbitrary safety factor may be too simplistic an approach because results in the animal may not be clearly translatable into an expected clinical effect in humans. Thus, additional considerations such as the calculated percentage receptor occupancy and “minimal anticipated biological effect level” (MABEL) based upon predicted plasma levels as a function of the in vitro biological effect ought also to be considered in setting the target dose. In drugs with significant potential toxicity, including cytotoxic agents for cancer treatment, the lethal dose in relevant animals is also used to assist in dose selection in man. To optimize the development program, translation of preclinical biomarkers of disease, as well as drug safety or efficacy to humans, is important to consider early. This process includes validation of the biomarker in the laboratory as well as qualification in humans to confirm its usefulness. The development of effective biomarkers as companion diagnostics to stratify an individual patient’s response in relation to a drug’s adverse events and disease responsiveness is important on our quest for personalized medicines. First-in-man studies generally involve single dose escalation in healthy young males. In this design, the first cohort of subjects receives the lowest dose, after which subsequent cohorts receive progressively higher doses, up to either a predefined top dose or the maximum tolerated level. Doses are initially escalated by a factor of between 2 to 4, then as one approaches the predefined top dose, escalation proceeds more cautiously with 1.5–2 fold increments. The exact dose escalation scheme will depend upon the drug’s target and off-target effects and will take into consideration the potential for any adverse effects and that the exposure and pharmacological effects on the subjects may not increase in proportion to the dose. The possibility of a nonlinear dose response, particularly a greaterthan-expected overproportional increase in drug effect or exposure, demands a cautious drug escalation regimen. Different subjects may be recruited to each escalation group, although sometimes the same subjects can be recruited to receive higher single doses using the so-called “leapfrog” design. However, repeated escalation in the same subject is not always appropriate as there is the potential for a carryover effect and development of an immune response to the drug (particularly with biological agents). Also, fewer subjects are exposed to the drug, limiting the safety data. There will be occasions when the use of healthy volunteers is not ethical or feasible, particularly when the potential for toxicity exists even at low doses, as with cytotoxic products, Regulatory Focus 39 or when disease-specific factors mean that data from healthy volunteers will have little relevance for the target patient population. These single dose studies are generally followed by administration of multiple doses either in an ascending or parallel design depending upon the potential risk factors. Phase 1a studies will also generate important pharmacokinetic data such as bioavailability, tissue exposure and dose linearity, as well as pharmacodynamic data on measurable target and off-target effects. These data will facilitate decisions such as the proposed dose and regimen and guide requirements for safety monitoring during later phase studies. Studies in healthy subjects can also be useful to assess the therapeutic effect in a human disease model by providing early proof of mechanism or principle; an example is pain models involving assessment of protection against pain induced by, e.g., UV sunburn, topical skin agents, or electrical stimulation of skin. Early phase studies will also allow comparison of human and animal pharmacokinetic and pharmacodynamic effects and any observed differences will clearly impact the planned doses for later studies. The appearance of significant amounts of a novel metabolites in humans compared to animals will necessitate further toxicological investigation. 40 March 2011 Late Phase 1 studies, known as Phase 1b studies, are useful in assessing the potential for drug accumulation and the relevance of potential biomarkers during later phase studies. Other Phase 1 studies that are generally non-rate-limiting include studies in special populations such as people with liver or renal disease or the elderly, drug interaction studies, ethnicity bridging and comparative bioavailability following formulation or manufacturing changes (particularly for biologicals). Patient safety, particularly in Phase 1 studies, is of the utmost importance and has been reviewed in the European guideline (EMEA/ CHMP/SWP/2837/07). Mitigation of risks is an important part of study planning and key measures need to be clearly documented in the study protocol and related documents. Suitable clinical trial sites (generally hospital-based for rapid access to emergency support) using experienced and well-trained staff are an important part of risk mitigation. Safety considerations will drive the study design by impacting population, dose selection (particularly starting and highest dose), route and rate of administration, number of subjects per dose, increment in each cohort, dosing sequence and interval of subjects within the same cohort, criteria for advancing to the next dose level and study stopping rules. The Phase 1 development program can often be accelerated by using a combined, so-called “fusion” protocol, which integrates elements of the Phase 1a and Phase 1b studies into one seamless adaptive study. This approach supports a single ethics and regulatory approval submission as well as the application of adaptive approaches in the conduct of the studies. It is our experience that such “fusion” studies can provide time savings of up to 30% and cost savings of up to 20%. ”Fusion” protocols require clear justification of the study design and detailed criteria for progressing, such as clear, pre-defined stop/go criteria at critical points. These fusion studies are best conducted in clinical pharmacology units where investigators, the local ethics committee and the government regulatory body already have experience with this approach. The progress of fusion studies can be further facilitated by conducting these at centers that have rapid access to patients in addition to healthy volunteers so as to facilitate rapid transition to the Phase Ib part of the study. Phase 2 Development Detailed assessment of the Phase 1 information is essential to support the Phase 2 program, which is generally designed to provide proof of concept and to select one or a maximum of two dosing schedules that will be investigated in the pivotal Phase 3 studies. By addressing potential issues during the preclinical and Phase 1 programs, many pitfalls of Phase 2 trials can be avoided. Applying adaptive trial design principles is particularly useful to accelerate the Phase 2 program. Sometimes it may even be possible to integrate components of the Phase 1 and 2 studies into a seamless “learning phase,” followed by a Phase 3 confirmatory program. This approach is often used in developing biologicals, orphan drugs and generics. Adaptive trial designs involve using data generated early in the study to guide and amend the future progress of the study. However, any changes to the ongoing study must adhere to strict predefined criteria to avoid introduction of bias. Furthermore, not all studies are suitable for an adaptive design. Examples of adaptive designs include: • studies that increase recruitment into the dosing arm(s) showing greater efficacy • repowering of studies based upon interim determination of the coefficient of variation for the blinded data • increasing recruitment of subpopulations that appear to respond to the trial therapy • discontinuing ineffective doses according to strictly predefined criteria • early stopping due to futility or obvious efficacy benefit over placebo; in this situation there will be an alpha CONFERENCES & EVENTS 23–24 March 2011 Preparing Compliant eCTD Submissions Rockville, MD RAPS.org/eCTD/march2011 7–8 April 2011 2011 RAPS Horizons Vancouver RAPS.org/Horizons2011 6–9 June 2011 RAPS Executive Development Program Kellogg School of Management Evanston, IL RAPS.org/exec/june2011 spend, meaning there is the potential to increase the total study population in the event the early stopping rules are not met There is significant controversy about the statistical robustness of adaptive designs and data analysis may involve a complex Bayesian statistical approach. Therefore, such studies are not generally accepted as part of a Phase 3 confirmatory program but are considered to have value during the early phases of development. The application of biomarkers in Phase 2 studies also is receiving considerable attention. The US Food and Drug Administration (FDA) Critical Path Initiative (Challenge and Opportunity on the Critical Path to New Medical Product, March 2004) and the recent update (Critical Path Report on Key Achievements, 2009) highlight the need for biomarker discovery to facilitate and speed up drug development. Furthermore, the European Medicines Agency and FDA recently concluded the first joint qualification process for biomarkers. Biomarkers are measurable characteristics that reflect physiological, pharmacological or disease processes. A biomarker may be a physiological measure, a soluble, tissue or genetic marker or an imaging endpoint. Generally, changes in biomarkers can be detected earlier and more readily than changes in the corresponding clinical endpoint. While biomarkers have limited use in confirmatory studies because they need to be validated, adequately qualified biomarkers can be extremely useful in dose selection. Early review of potential biomarkers is an important component of the overall development program so that they can be used to support early go/no-go decisions and differentiate responder from non-responder populations. The Regulatory Focus 41 latter could be run as a parallel program to support the development of companion diagnostics and personalized treatment of individuals. Biomarkers are not a new concept and a number are well accepted: • blood pressure for cardiovascular diseases • HbA1c for diabetes • bone mineral density for osteoporosis • CD4 count for HIV • viral load for Hepatitis B and C • antibody titer for autoimmune disease or post vaccination • MRI for multiple sclerosis With the development of proteomics and genomics, substantial new knowledge about biomarkers and disease drug targets is being generated, which promises to broaden the utility of biomarkers in clinical development. As a consequence, a number of innovative biomarkers have been introduced into drug development, some examples include: • pharmacogenomic markers • histology/histochemistry • PET imaging endpoints in oncology • • • serum biomarkers and imaging of unstable atherosclerotic plaque in cardiovascular disease imaging and biochemical markers of early neurodegenerative diseases (e.g., mild Alzheimer’s disease) osteoarthritis skeletal biomarkers Conclusions Drug development is complex. Early acquisition of knowledge is critical to enable clear, predefined stop/go criteria at critical points in the program to ensure progression or discontinuation in a timely manner to minimize financial loss. The primary development challenge for the biopharmaceutical industry is to ensure that Phase 2 trials are adequately sized, rigorously designed and conducted and thoroughly analyzed to reasonably judge the chance of success in the later stages of development. Sound scientific data should form the basis of any decision about transitioning a drug to Phase 3. If internal resources are not available, partnering with an experienced drug development company can provide the services and guidance needed to navigate the clinical trial process and help bring a new product to market. A development services company with knowledge and expertise in biotechnology and the appropriate therapeutic area can help its biopharmaceutical partner design clinical trial protocols that produce all relevant data as quickly and efficiently as possible. Perhaps most importantly, an outside company can provide an unbiased analysis of the data, which should form the basis for informed and pragmatic decision making about which drug candidates should move forward. Some of the key success factors in early clinical development are detailed knowledge of the relevant regulatory, therapeutic and disease guidelines, early development of data using adaptive study designs and modeling/ simulation and application of biomarkers, disease models and early patient exposure (where relevant). A clear development strategy defining all the relevant points for the program review, including regulatory interactions, is crucial. Safety is clearly of critical importance and risk mitigation planning along all parts of the development is essential. Authors Cecil Nick, BSc (Hons.) FTOPRA, is vice president, biotechnology at PAREXEL Consulting. Nick provides expert consulting services to clients particularly on the clinical and regulatory development of biotech and biological products. He has been involved in the development and regulatory approval of a number of innovative and biosimilar medicinal products. Dr. John Lambert, MD, PhD, is vice president and chief medical officer of PAREXEL Early Phase, based in London. He graduated in Medicine from Melbourne University, Australia. He is board certified in Gastroenterology, Internal Medicine and Clinical Pharmacology having trained in Melbourne, Toronto and the UK. 42 March 2011