From: Cynthia_Letizia@vrtx.com Sent: Friday, March 14, 2003 4:37 PM To: fdadockets@oc.fda.gov Subject: Docket 02D-0492 Comments Dear Sir or Madam, Please find below comments from Vertex Pharmaceuticals, Inc for the draft guidance published in Docket No. 02D-0492: "Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers" Thank you for the opportunity to comment on this significant guidance document. Sincerely, Cynthia Letizia, MPH, RAC Director Regulatory Affairs Vertex Pharmaceuticals Incorporated 130 Waverly Street Cambridge, MA 02139-4242 Tel: 617.444.6836 ? Fax: 617.444.6803 cynthia_letizia@vrtx.com Comments on draft FDA guidance for industry and reviewers on(strikethrough: :) "Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers"  [DOCKET No. 02D-0492] The effort of the agency to develop recommendations for estimation of human equivalents based on evaluation of toxicokinetic data from nonhuman species is applauded.  These issues have been of longstanding considerable debate and allometric scaling techniques must be applied with caveats regarding assumptions and limitations.  Comments are submitted for consideration in order to clarify specific issues and terminology.  Page 4, Line 147:  The definition of NOAEL is ambiguous.  The definition should state that "NOAEL is the highest dose that does not result in a significantly greater incidence of adverse effects in comparison to vehicle controls." Page 5, Line 167:  The statement: "Measurements of systemic levels of exposure (i.e. AUC or Cmax) cannot be employed for setting a safe starting dose in humans, and it is critical to rely on dose and observed toxic response data from adequate and well-conducted toxicology studies." is not a reflection of the current thinking of integrating pharmacokinetics into toxicology. It is generally accepted that pharmacological (and toxicological) effects are manifestations of biochemical phenomena, and that fundamentally biochemical phenomena are the result of biochemical reactions that follow the Law of Mass Action, according to which the driving force in a chemical reaction is a function of the concentration of the reactants.  The problem of course is that it is usually not possible to identify the concentration at the effect site, and therefore reliance must be made on surrogates of exposure at the effect site.  As exposure in any given tissue can be expected to correlate better with measures of plasma exposure than with simply dose, it is reasonable to expect that Cmax and especially AUC will be better surrogates of the toxicologically relevant exposure than administered dose (particularly when the dose is not administered intravenously).  The use of exposure metrics such as Cmax and AUC is even more crucial when the drug exposure is not increasing with increasing dose.  This is often the case with many small molecule compounds discovered using structure-based drug design Page 5, Line 195:  One cannot agree with the statement that: "Toxic endpoints for therapeutics administered systemically to animals, such as the MTD and NOAEL, are usually assumed to scale well between species when doses are normalized to body surface area."  This statement is in fact refuted by subsequent statements in the same paragraph.  First, as stated in the subsequent sentences, this statement is based on the analysis of MTDs for a set of antineoplastic drugs, and that a subsequent analysis found that the MTDs scale best when doses are normalized to W0.75, instead of W0.67 (inherent in body surface area normalization).  Despite this, the Draft Guidance recommends scaling based on body surface area, based on the rationale that scaling by W0.67 provides "a more conservative starting dose estimate."  Arguably  this rationale cannot be defended, as scaling by W0.7 or W0.65 also provide "more conservative" estimates, and the rationale for picking one of these dose normalization factors is just as strong (or weak) as the W 0.67 factor.  In essence there is no underlying physiological or mechanistic basis for scaling by body surface area.  The suggested methodology already provides for incorporating conservativeness through a Safety Factor (suggested value of 10).  Incorporation of conservativeness through a Safety Factor is preferred, as this approach renders the extent of conservativeness more explicit. Page 6, Line 198:  The statement "The basis for this assumption lies in the work of Freireich et al. (1996) and Schein et al. (1970) ?" implies that NOAELs for non-oncology agents are will scale similarly to MTDs for oncology agents.  This is a very broad assumption.    As this assumption provides the underpinning for the recommendation in the Draft Guidance's that NOAEL be scaled according to body surface area, the recommendation is questionable. Page 7, Line 245: The statement:"To consider mg/kg scaling for a therapeutic, the available data should show that the NOAEL occurs at a similar mg/kg dose across species." holds mg/kg scaling to a different standard than mg/m2 scaling, and cannot be scientifically justified. Page 7, Line 249:  The statement: "If these factors cannot be met, the mg/m2 scaling approach for determining the HED should be followed as it will lead to a safer MRSD", does not account for the possibility that allometric scaling of PK parameters will result in an exponent of less than 0.67, and therefore result in an even more conservative estimate of MRSD. Page 7, Line 256:  The recommendation to scale NOAEL by W0.94 assumes that the concentration at the site of GI toxicity correlates better with the concentration in the lumen, and not the concentration in the gut wall (which may not be the case, as it is possible that the latter correlates better with plasma concentration). Page 15, Line 519:  There is no reference provided for the statement that: "? there is evidence that the area under the plasma concentration time curves in rats and humans correlates reasonably well when the doses are normalized to mg/m2."  First, scaling factors other than W could arguably provide better correlations over the set of available data for all drugs.  Second, if the purpose is to estimate the AUC in humans associated with the NOAEL AUC in animals, it should be preferable to simply estimate the human CL of the agent being investigated, and scale the NOAEL based on this PK parameter. Page 15, Line 525:  The statement "there are no data to suggest a superior method for converting NOAELs" could be inverted to read, t "there are no data to suggest that scaling by body surface area is superior to other methods, such as scaling based on exposure (AUC and Cmax) calculated from allometrically estimated PK parameters".  The statement in the Draft Guidance also neglects to define "superior."  If the definition of "superior" is based on safety, then scaling by W0.60 is "superior" to scaling based on body surface area, as it will provide more conservative estimates of MSRD.