SDG llc

Shortening the path from laboratory to patient

Allan M. Green, MD, PhD, JD

Lee S. Simon, MD

In the last few years it has become apparent that introduction of new drug products has not kept pace with increases in fundamental biological knowledge nor the development of multiple supporting technologies that were expected to fuel a surge in drug development. Genomics and proteomics have lead to significant advances in basic knowledge. High throughput screening and combinatorial chemistry have provided powerful new tools to support drug discovery. Yet the number of IND filings and the number of approvals of new chemical entities has actually fallen in recent years. To address this problem, the United States Food and Drug Administration (FDA) has undertaken its own study of the issues limiting successful clinical drug development, and has embarked on what is known as the critical path initiative. In the FDA terms, the “critical path” for drug development are those steps which take a potential drug candidates from preclinical study through human investigation. Thus the Critical Path project includes study of the tools and strategies for “proof-of-principle” studies or, as they are sometimes known, “first-in-human” studies. Such studies are typically critical in determining whether to move clinical development forward and whether funding for further clinical study can be obtained.

In line with the critical path initiative, FDA has recently issued two new guidance documents intended to speed the earliest clinical studies of new drug candidates in people. In these new guidance documents entitled “exploratory IND studies” and “ IND’s - approaches to complying with CGMP during phase I” FDA lays out the minimum appropriate information that they will require to evaluate the safety of potential new compounds for initial human studies. In our opinion, these new guidance documents reduce both the time and cost of moving new therapeutic candidates into human proof-of- principle studies. As we explain below, the cost savings is realized by simplified preclinical toxicology requirements, reduced requirements for the amount of drug substance that must be manufactured and consequent manufacturing cost savings and the savings of six to twelve months to the start of phase one human testing. These advantages may be of most significance to projects in which multiple related drug candidates must be evaluated for comparative pharmacokinetic or pharmacodynamic characteristics, in which preclinical biodistribution must be confirmed in human studies, or in which early evidence of pharmacologic effect in humans must be demonstrated to move a program forward.

In the New Guidance documents, the FDA has expressed the specific concern that “potentially effective candidates may not be developed because of resource constraints;” and the new Exploratory IND has been designed to maintain “needed human subject protection” while at the same time requiring “fewer resources than is customary” for a traditional IND.

The agency explicitly has noted that nine out of ten experimental drugs fail “because we cannot accurately predict how they will behave in people based on laboratory and animal studies.” What appears to be “promising” in vitro or in a preclinical model is too often unacceptable in human use. The new Exploratory IND concept has been specifically developed to allow early stage R&D programs to test multiple related candidate agents in vivo in humans to avoid the pitfalls of relying on imperfect in vitro systems or animal models to select an agent for further clinical development.

In order to facilitate more rapid and more informed proof-of-principle testing in humans, the FDA has specifically recognized that “very early exploratory scientific studies in people” can be conducted more expeditiously for two reasons: i) only small amounts of drugs may be used in early studies, limiting the risk for subjects in such early trials and/or ii) such trials involve “dosing a limited number of subjects with a limited range of doses for a limited period of time.”

So the key characteristic of exploratory IND’s is that they anticipate administering either subpharmacologic doses of an experimental product or doses expected to produce a pharmacologic, but not a toxic, effect. The exposure of human subjects is intended to be limited to seven days or less. Perhaps most important, studies in an Exploratory IND are not expected to explore or establish maximum tolerated doses of a new agent. Thus, compared to a traditional IND, studies in an Exploratory IND are expected to pose minimal risk to experimental subjects and, accordingly, the preclinical safety requirements have been somewhat reduced.

Preclinical Safety Studies required for an Exploratory IND depend on the nature of the study design. All safety studies must be performed under GLP conditions. Two basic study designs are envisioned: those employing “microdoses” of new agents and those employing doses intended to produce a pharmacologic effect.

A. Microdose studies: A microdose is defined as less than 1/100th of the dose of a substance calculated, based on animal data, to yield a pharmacologic effect (with a maximum of 100 micrograms for a small molecule or 30 nanomoles for a protein). Human studies employing microdoses can be supported with single dose toxicity studies in a single mammalian species, if justified by in vitro metabolism data and comparative data on in vitro pharmacodynamic effects. In other words, the sponsor should demonstrate that a one hundred-fold multiple of the proposed human dose (based on body surface area) does not produce adverse effects in experimental animals. If no overt pathology is seen, histopathology is needed only for high dose animals and controls. Genotoxicity studies are not required.

B. Studies of pharmacologic effects of candidate agents: Since these studies would not be expected to establish maximum tolerated doses, repeat dose clinical trials lasting up to seven (7) days can be supported by a two week repeat dose toxicology study in a sensitive species with toxocokinetic studies. The rat would be expected to be used most often, with a second species used to confirm that the rodent species selected is appropriately sensitive. Only four non-rodents per treatment group are required for the non-rodent species and repeat administration of drug is only necessary at the single dose level approximating the rodent no adverse effect level. Thus, there may be a significant saving in time and cost of the toxicology study and in the amount of material that must be manufactured for such a study. Safety pharmacology (CNS, respiratory and cardiovascular) is necessary prior to human testing. Genotoxicity testing is required unless only terminally ill patients will be studied.

GMP manufacturing conditions are required for any drug substance intended for human use. However, the Exploratory IND paradigm relaxes the amount of study which must be performed under such rules. For example, a certificate of analysis may be used for lots employed in toxicology testing to document identification, purity and potency of the material. Stability information need only cover a period long enough to assure product quality during toxicology testing and the intended early human clinical studies. If the same batch of GMP material is used for toxicology and clinical study, it may be qualified by id, purity and potency testing; not all impurities need be characterized unless an issue arises during toxicology testing. If multiple batches are uysed for toxicology and clinical study, analytic testing is needed to assure that the batch used for clinical testing is representative of the batches used for preclinical study.

FDA has encouraged the identification of technologies for simplifying compliance with cGMP requirements. For example, they encourage the use of prepackaged water for injection and presterilized containers to avoid the need for validation of those systems. They encourage the use fo disposable equipment and process aids to reduce the cleaning burden and cleaning validation. They encourage the use of process equipment that is closed to alleviate the need for strict clean room classification. And they encourage the use of contract or shared production and testing facilities to reduce the burden of establishing appropriate quality systems and record-keeping.

The Exploratory IND paradigm is expected to be most useful in those circumstances in which microdose studies may be used to develop new imaging agents; for classic single and multiple dose pharmacokinetic studies; to document the relationship of molecular target expression with pharmacodynamic endpoints; for pharmacodynamic studies; and for the confirmation in humans of preclinical evidence of efficacy. Data for multiple related compounds can be submitted in a single exploratory IND submission. Procedurally, on completion of the E-IND clinical studies, FDA expects the sponsor to withdraw the E-IND and submit a traditional IND in order to proceed to conventional phase I and phase II dose escalation and efficacy studies.

It is not clear how well the E-IND paradigm will apply to biological products. Recent evidence that even initial low doses of biological materials can lead to severe side effects in humans which cannot be well predicted by traditional preclinical animal studies may lead to caution by FDA in adopting a simplified preclinical safety package for such agents. However, for small molecules the E-IND process may reduce the time required for first-in-human studies by 6 to 12 months.