Draft Guidance Consistent With a Tougher FDA

April 9, 2010

The “new” FDA’s latest Draft Guidance suggests that the agency is arguably broadening the scope of pre-market clinical studies for investigational drugs. In its “Pharmacokinetics in Patients with Impaired Renal Function – Study Design, Data Analysis, and Impact on Dosing and Labeling,” March, 2010, the agency “provides recommendations on when studies should be conducted to assess the influence of renal impairment on the pharmacokinetics (‘PK’) of an investigational drug, the design of PK studies, and how such studies should be carried out.” The primary goal of such studies is “to determine whether the PK is altered to such an extent that the dosage should be adjusted from the dose(s) established in the phase 3 trials.”

Pharmacokinetics refers to the effect of the body upon a drug – as distinct from pharmacodynamics, the effects of the drug upon the body. PK includes the drug’s mechanisms of absorption and distribution, the rate at which it acts and its duration of action, how the compound is metabolized, and the effects and routes of its excretion. Many drugs are excreted by the kidneys. Patients with renal insufficiency may excrete drug more slowly and/or less completely than patients with normal renal function. In kidney failure patients, the extent of protein binding – and hence of bioavailability, and hence of pharmacologic effect – may also vary. Making all the determinations and calculations called for in the new Guidance will require substantial time, effort, and expense. Given the rising prevalence of disorders that may be complicated by kidney failure, including hypertension and more especially diabetes, the burden of compliance with the Guidance is likely to increase over time.

The agency calls for PK studies on all drugs prescribed for chronic use in renal failure, and on some (antibiotics, e.g.) to be used only acutely. FDA also calls for such studies of therapeutic biologics (e.g. proteins) with molecular weight <69,000 to be used in kidney failure patients. For end-stage renal disease “patients undergoing dialysis, PK should be studied under both dialysis and non-dialysis conditions to determine the extent to which dialysis contributes to the elimination of the drug and potentially active metabolites.”

In discussing details of the studies it recommends, FDA specifies the make-up of the control group to use, what sorts of data it wants to see, and what to do to generate sufficient information on patients on both hemodialysis and peritoneal dialysis. Once these data are available, the agency wants them to be analyzed to ascertain what if any recommendations should be made for dosage modification in kidney failure patients. The agency calls for estimation of PK parameters, such as plasma and urinary concentrations, drug clearance rates, the area under the concentration-time curve, volumes of distribution, half-lives, etc.; mathematical modeling of the relationship between those parameters and measures of renal function; and development of dosing recommendations. “If there is a need for dosage adjustment in patients with renal impairment… the adjustments [should be] described either globally or based on estimated glomerular filtration rate (eGFR) or estimated creatinine clearance (CLcr).” These estimates are both measures of kidney function. The draft Guidance provides an array of formulas to make these calculations. For those pharmaceuticals or their active metabolites that “exhibit[] nonlinear or time-dependent PK,” FDA calls for a multiple-dose study, as opposed to single-dose studies, in which the same dose is administered to all patients.

Depending on what is learned from the data and from analyzing them, it may be appropriate to modify the package insert, including Highlights of Prescribing Information, the Contraindications section, or the Warnings and Precautions section, perhaps with a cross reference to the Dosage and Administration section. Where known, “the Overdosage section could note the extent of elimination by hemodialysis and whether hemodialysis is (or is not) known to be useful in treating an overdose.”

For drugs excreted by the liver rather than by the kidney, FDA may accept a “reduced PK study” of the drug’s metabolism. If no difference is observed between those with end-stage renal disease and those with normal kidney function, a full study is unnecessary. Otherwise, however, such a study is called for, even though the kidney’s metabolic role is comparatively modest.

As a draft Guidance, the document does “not establish legally enforceable responsibilities. Instead [it] describe[s] the Agency’s current thinking on a topic and should be viewed only as recommendations…” Nevertheless, the approach taken comports with other recent FDA changes suggesting enhanced scrutiny of new drug approvals. Companies should remain alert for other developments likely to affect their operations, as more are highly likely, and they may well continue to increase the stringency of the regulatory regime.