Every compound poses its own unique issues, and each development program must balance a wide range of scientific, ethical and business considerations to safely and efficiently provide data necessary for a decision to embark on late phase studies or global registration.
First Time in Humans
Every new clinical entity heading for regulatory approval has to start human clinical trials somewhere, and of course your initial protocol needs to be included in your Investigational New Drug application and meet with both Agency and Institutional Review Board approval.
The safety of the participants is always the primary concern, while seeking to provide you with the pharmacokinetic and/or pharmacodynamic data needed for a decision regarding further compound development.
There are many issues. Even with good preclinical toxicology data, extrapolating to humans may not be straightforward, especially if there are considerable differences between species. Should you use a microdose strategy? Should you be looking for genomics markers? What is the best starting dose? What should you plan as the range of doses? When do you want to draw your PK samples? What safety and pharmacodynamic parameters need to be monitored? If specialized assays or equipment are being considered, are they cost effective? What should be your cohort size? Do you need placebo recipients, and what should be the active:placebo ratio? What are your stop dose criteria, and who should be involved with the safety monitoring and dose escalation decisions? And of course the Inclusion/Exclusion criteria need to strike a balance allowing feasible recruitment while avoiding confounding variables.
Beyond the traditional Single Ascending Dose then Multiple Ascending Dose protocol designs, there are multiple options including “adaptive” and hybrid designs, use of “sentinel” subjects, overlapping cohorts, incorporation of women, elderly, or other special populations, and early inclusion of patients with a target indication for incorporation of biomarkers. Appropriate use of strategies such as these can deliver data with proof of concept far sooner than traditional methods.
We see a large clinical need for our emerging biologic compounds, with their target specificity, unique mechanisms, and novel therapeutic potential. Fortunately, our increasing understanding and utilization of genomics, proteomics and molecular biology provides many promising compounds.
Yet as is generally recognized, our approach to clinical trials with biologics will be permanently affected by the very serious adverse events that occurred in connection with TGN412 during its first time in humans administration March 13, 2006. And rightfully so, as that experience illustrates important lessons regarding use of the Minimal Anticipated Biologic Effect Level (MABEL) as well as the No Observable Adverse Effects Level (NOAEL) in determining our starting dose, and more thorough scrutiny of the study design and safety precautions in general in relationship to the compoundís mechanism of action.
With respect for these principles, Dr. Ruckle’s experience as Investigator includes 8 First Time In Humans clinical trials with biologics conducted safely since March 2006, and as a consultant for First Time In Humans studies for both large and small molecules. Pacific Pharma Group, LLC is prepared to assist with your protocol design, especially your First Time In Humans trial, and your product development strategy from IND through Proof of Concept.
Stakeholders in the drug development process generally agree that both the time and expense required to move a new chemical entity from drug discovery to approval are too great, and seek various solutions to expedite the process. One solution is the utilization of “microdose” studies. After several years of discussion, the FDA published guidance in January 2006 regarding use of microdose studies, including an exploratory IND (expIND) regulatory framework particularly suited to early compound selection.
One attractive feature of microdose studies is the ability to obtain human data early, at low risk to participants. A microdose is defined as “1/100th of the amount expected to have a pharmacological effect, up to 100 micrograms.” Doses in this range require very sensitive assays, which may exceed the limits of “wet lab” methods such as LC/MS/MS. However, with an isotope such as 14C and utilization of accelerator mass spectrometry (AMS), the threshold of detection is generally sensitive enough for useful data following administration of nanogram level doses of the study drug.
Medications for selected indications may require particular pharmacokinetic profiles for safety and efficacy, especially anti-infectives and certain CNS and cardiovascular products. Animal models may or may not accurately predict human pharmacokinetics, and approximately 25% of new chemical entities fail to reach or demonstrate proof of concept due to an undesirable PK profile. Microdose studies under an expIND have been successful in providing sufficient human PK data to allow decision making regarding compound selection and prioritizing further development, thus saving time and money compared with conventional tools, and the data may guide your First Time In Humans study design under a conventional IND.
In addition, AMS and microdose technology may be useful tools to answer questions beyond compound selection. Microdose studies may document penetration into crucial target tissue compartments of distribution. Also, when combined or compared with a larger “cold” dose, microdose technology may define absolute bioavailability to guide further formulation development. And, if a small labeled dose is combined with a conventional dose during an otherwise conventional Phase I study, AMS technology allows determination of mass balance and can indicate the presence or absence of unique human metabolites.
Dr. Ruckle has been an active participant in the dialogue regarding microdose studies since 2005, when he conducted his first 14C labeled microdose study. Pacific Pharma Group, LLC is prepared to help you weigh the pros and cons of utilizing microdose technology as part of your compound development strategy.
Japanese Bridging Studies
As the world’s second largest market, Japan is an attractive and important consideration when planning your global development strategy. Yet the path to registration has unique regulatory hurdles, and must be approached with appreciation and sensitivity for Japanís cultural and ethnic concerns.
Drug development within and for Japan has changed markedly since implementation of the ICH Guidelines in 1998. In particular, Section E5 outlines general guidance for use of foreign data, which led to ìbridging studiesî comparing the pharmacokinetics, safety and tolerability of compounds in Japanese individuals versus Caucasians or other reference populations. Such studies allowed a shorter and focused development program in Japan to confirm safety and efficacy.
Although these guidelines have facilitated approval of numerous compounds, a 2 to 3 year lag still typically exists between a compound’s registration in Japan in comparison to its first approval elsewhere.
Beyond the “bridging” strategies of the past 10 years, there is increasing interest in concurrent global development regardless of site of origin of the investigational compound. Whether “bridging” data from one jurisdiction to the other, or planning a concurrent global development program, multi-national programs require thoughtful design and execution.
Dr. Ruckle began as a Principal Investigator for Japanese-Caucasian bridging studies in July, 1998, as the E5 guidelines were first approved, and has performed over 50 bridging studies for Japanese registration since, including studies allowing concurrent development in Japan, the US, and the EU. Study experience encompasses a wide variety of compounds, clinical indications, and study designs. Coupled with liaisons in Japan, our proven track record prepares us to assist in this dynamic arena.
Special Patient Populations
Traditionally, new chemical entities expected to have low toxicity and thus low risk for the participants have been studied in “normal healthy” subjects, usually male, often age 18-45, and (depending on the location of the research unit) primarily Caucasian or Hispanic. While understandable and fairly easy to recruit, the disadvantage is that there are many people in this world who are considerably different from this population, thus the pharmacokinetic or pharmacodynamic data from these studies may not directly apply.
At the other end of the spectrum, new chemical entities expected to have dose related toxicities such as cytotoxic cancer chemotherapy agents were largely studied in patient populations where the ethical considerations of the risk:benefit ratio required some potential for benefit to offset the possible risks. While also understandable, such studies are typically very difficult and time consuming to recruit.
Fortunately there are a variety of alternatives. Most stakeholders recognize the benefit of including a population more diverse than healthy normal young males. Especially with the global trend towards an aging population, the upper age is more typically 50 to 65, and there is more interest in earlier inclusion of women- with appropriate pregnancy precautions to avoid unintended fetal exposure. And as the industry becomes increasingly global, inclusion of Asians and other non-Caucasians is a growing priority.
Earlier inclusion of patients with the target indication is also of increasing interest, at times even in the First Time In Humans study, sometimes as a subset of the total enrollment. Adverse events and basic pharmacokinetic characteristics may both be somewhat different in patients than in normal healthy individuals, and many pharmacodynamic markers cannot be reliably assessed in healthy individuals compared with patients with the target indication. These data may be crucial early in compound development for a well considered decision regarding further compound development.
Dr. Ruckle has experience with study design and conduct involving a variety of special populations: women, Japanese/Asians, healthy elderly, pediatrics, women after menopause, and patients with Diabetes, Hypertension, Obesity, Hyperlipidemia, Osteoporosis, Osteoarthritis, Asthma, Renal Insufficiency, Hepatic Insufficiency, dry eyes, psoriasis, and etc. In collaboration with specialists in the appropriate clinical domain, Pacific Pharma Group is prepared to discuss your target population.
Asian Population Studies
Global development strategies increasingly include China, Korea, Taiwan, and other East Asian countries. Although the regulatory pathway is not as well defined and traveled as for Japan, as a member of ICH, the issues are generally similar.
Additionally, studies with Asian populations are increasingly important for FDA approval, because:
- The US Asian population is increasing;
- Asians have traditionally been under represented in US clinical trials; and
- Asian populations represent considerable diversity, including heterogeneity of CYP and other pharmacologically relevant enzymes such that they may require adjustments in the recommended dose of substrate medications.
Whether your strategy requires Asian populations with the intent of Asian registration, US labeling, or both, Pacific Pharma Group, LLC has the relevant experience to provide guidance.
An estimated 68% of Americans routinely use vitamins or some other dietary supplement, and there is an increasing expansion of a ìwellness industryî incorporating supplements and a variety of complementary and alternative interventions outside contemporary health care and the pharmaceutical industry. In the US alone, this consumer driven industry accounted for about $200 Billion in sales in 2002, and is expected to reach the Trillion dollar level by approximately 2012.
For our purposes, ìnutraceuticalsî refers to vitamins, minerals, teas, herbs, food extracts, and related products derived from nature, often intended as much to maintain health, prevent disease and promote wellness as to treat a specific illness.
Many companies are drawn to this market, yet the scientific foundation for understanding and appropriate utilization of nutraceuticals is relatively sparse by Western standards, especially in contrast to the scrutiny required to approve new chemical entities. While many individuals respect the collective wisdom of centuries of observations by traditional healers, and others may be encouraged by anecdotal examples, most within the scientific and medical communities call for additional data, from the level of chemical characterization and basic cellular mechanisms to the level of controlled clinical trials.
Studies with nutraceuticals pose a number of challenges. The ëstudy drugí is rarely a single chemical entity, and formulation may depend on “Good Agricultural Practice”î as well as “Good Manufacturing Practices.” Many compounds are non-proprietary and the compound is not intended for FDA registration as a medication to treat a specific indication, thus there is no Form 1572. This involves a different regulatory environment and a different economic environment, where research leans towards smaller studies with smaller budgets, and the outcome is a publication of a pure scientific observation or to describe a possible structure or function claim.
Still, the discipline, principles, and ethics of contemporary clinical research apply in this domain if the data are to be helpful. Studies must be done consistent with the Declaration of Helsinki, including appropriate informed consent and IRB approval. Pacific Pharma Group, LLC is prepared to assist with your nutraceutical studies with:
- Study design
- Protocol writing
- Informed consent writing
- IRB submission
- Site selection for study conduct
- Design of source documents and case report forms
- Data analysis
- Report writing
- Manuscript preparation