Changes to the US Food and Drug Administration’s pharmacogenomics draft guidance will likely be modest as the agency puts the finishing touches on the document after meeting with drug makers at least two more times ahead of the June 30 guidance release date, according to Chris Webster, chairman of the genomics division at the Pharmaceutical Researchers and Manufacturers of America.
Webster, who is also director of regulatory affairs at Millennium Pharmaceuticals, didn’t detail what changes the FDA would implement, he did say that one portion of the guidance the agency plans to “address” is the Interdisciplinary Pharmacogenomics Review Group, or IPRG, which will oversee voluntary pharmacogenomics data submissions. This has been a contentious component among drug makers since the draft was releases last November.
However, the FDA will not address this issue through the guidance, Webster said. Instead, the agency intends to release “essentially a standard operating procedure that will define the role, function, and composition” of the group.
Webster said the FDA will probably discuss the draft with drug makers at two upcoming events: the Biotechnology Industry Organization’s annual convention, which will be held June 6-9 in San Francisco, and the Drug Information Association’s annual meeting in Washington, DC, June 13-17.
Both meetings will provide last-minute opportunities for drug makers to pump the FDA for information about the guidance, and for the FDA to take in industry’s concern for some of the more controversial portions of the document.
Webster also said it is even possible that the pharmacogenomics guidance will be published around the time of the DIA meeting.
Asked to define some of the biggest points in the draft on which he’d want the FDA to focus, Webster, a former regulatory official at Pfizer, listed biomarkers and the “terms of reference” for the IPRG. According to the draft guidance, the IPRG will “review [voluntary genomic data submissions], to work on ongoing policy development, and to advise review divisions dealing with pharmacogenomic data.”
“It will be tweaking,” Webster told Pharmacogenomics Reporter during an hour-long interview at a Times Square hotel last week. “Don’t look for there to be anything spectacularly new. It could be refinement and going into more detail, and maybe a little bit of restructuring the organization of the guidance document itself.”
Addressing the Issues
To get a sense of the kind changes the FDA may inject into its draft guidance, it may help to read PhRMA’s suggestions to the agency. In the letter, submitted Feb. 2 — the last day for comment in a 90-day period — PhRMA focused on biomarkers, VGDSs, and the IPRG that will oversee them. (In all, 10 drug makers submitted suggestions to the FDA ahead of its Feb. 2 deadline for comments [read industry comments in their entirety here).
On the biomarker side, PhRMA, whose members contribute more than $30 billion annually toward drug discovery and development, said the definition of different biomarkers “is confusing,” and suggests devising three tiers of biomarkers: “biological marker,” which is “measured objectively and evaluated as an indicator of normal physiological processes, pathological processes, or pharmacological responses; “established biomarker,” which is “measured in an analytical test system with externally validated performance characteristics, and for which there is a compelling scientific framework or body of evidence that elucidates the biological significance of the test results; and “emergent biomarker,” which is measured in an analytical test system with externally validated performance characteristics, and for which there appears to be coherent scientific framework or body of evidence that elucidates biological significance of the test results.”
“In this case,” PhRMA said in its letter, “there is no ‘valid biomarker,’ because an ‘invalid biomarker’ would be meaningless … “
The industry group went on to urge the FDA to “define a process by which sponsors could prospectively gain a commitment that a particular biomarker would be accepted for regulatory decision-making.”
Significantly, in a statement aimed at boosting the idea of theranostics, PhRMA said the guidance “should also clarify whether the availability of an approved in vitro diagnostic or CLIA test is relevant to the determination that a biomarker is a ‘known valid biomarker’ for regulatory decision-making.”
On the VGDS front, PhRMA said it believes the FDA’s position is unclear, and suggests “many aspects” of it “be described in greater detail. For instance, ‘What will be the composition (expertises represented, affiliations, etc.) and terms of reference of the IRPG?” PhRMA said “it is not clear to us that, due to the highly technical nature of much of pharmacogenomics, these functions could be assumed readily by any of FDA’s existing advisory committee.”
In addition, “Since the VGDSs will be reviewed by the IPRG as well as the relevant review division, we recommend that FDA should give more information in the guidance about how the confidentiality of VGDS submissions will be ensured, and any conflicts of interest managed, if the management of the IPRG includes those who are not employees of the FDA, or who may not be accustomed to working under strict confidentiality imposed by the FDA’s review divisions.”
PhRMA also asked to know what the relationship between the IPRG and the FDA review division will be. “The draft guidance states that ‘VGDS filings will be analyzed by the [IPRG] and the relevant review division staff,’ but this does not clarify whether the review division staff will conduct their analysis independently of the IPRG or will effectively become members of the IPRG for that discussion. Since VGDS submissions will be reviewed by both groups, what will be their respective and complementary roles?”
Finally, PhRMA said “the value to sponsors of using the VGDS process is not clearly stated in the draft guidance, beyond the assertion that the submission of data under VGDS will help to educate agency staff as to how pharmacogenomics techniques are being used in drug development.
“While we strongly support FDA in its efforts to keep its staff aware of new technological approaches, we believe that there should be more concrete and specific benefits for the individual sponsor, who may expend considerable resources in preparing a voluntary submission,” PhRMA said.
The industry group also stressed that the pharmacogenomics draft is “a potentially powerful system” for helping other regulatory agencies begin considering pharmacogenomics technologies and data more intently.
“We recommend that the FDA should discuss this approach with the international regulatory authorities, especially those in Canada, the European Union, and Japan, so that equivalent or cooperative systems could be established” there, PhRMA said in its letter.
The agency must have listened: According to Millennium’s Webster, on the morning of June 17 during the DIA meeting, Larry Lesko, director of the agency’s Office of Clinical Pharmacology & Biopharmaceutics; Ron Salerno, director of experimental medicine and worldwide regulatory affairs at Wyeth Research; and officials from European and Japanese regulatory agencies will “look into the international context” of the pharmacogenomics guidance.
Additionally, Spiros Vamvakas, principal scientific administrator of EMEA’s scientific advice and orphan drug sector, was invited to give “an overview of a future EU PGx guidance document that may replicate some of the features of the FDA’s process,” said Webster.
He added there will also be discussions of whether any aspects of the FDA’s guidance “should be harmonized under [the International Conference on Harmonization] at this point.”