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									                                                                                                                         Update 2008, Issue 5
                                                                                                                         With Permission from FDLI,

     Personalized Medicine

            Collecting and Testing Samples
            for Pharmacogenomic Research:
            Issues for Manufacturers of Drug and Biological Products
            by Grail Sipes

          Pharmacogenomics has been characterized as “the study of             In March 2008, FDA’s Pharmaceutical Science and
        variations in DNA and RNA characteristics as related to drug        Clinical Pharmacology Advisory Committee recommended
        response.”1 At the most basic level, pharmacogenomics is the        that to facilitate pharmacogenomic research, clinical trial
        study of how genes affect the way people respond to drugs,          sponsors should collect DNA samples from all participants
        and pharmacogenomic research is a critical component in the         in clinical trials (whether Phase I, Phase II or Phase III).4
        development of personalized medicine.                                  In light of these regulatory initiatives, it is likely that drug
          To facilitate this research, the Food and Drug Administra-        and biologic manufacturers will increasingly be involved in
        tion (FDA) issued a guidance document in 2005 establishing          the collection and testing of blood and other tissue samples
        a framework for industry’s submission of pharmacogenomic            from clinical trial subjects. These activities are governed by
        data in connection with the approval of drug and biological         a broad range of legal and regulatory requirements with
                                                                            implications ranging from product approval to the sponsor’s
        products. This guidance included a special pathway — the
                                                                            liability exposure. This article will address a number of
        voluntary genomic data submission (VGDS) — for early-stage
                                                                            important questions related to research on human tissue
        or exploratory data.2
                                                                            samples, including: Does the sponsor have adequate consent?
          FDA has also developed an internal concept paper setting
                                                                            Have privacy concerns been addressed? And who owns these
        out strategies for the use of pharmacogenomic data in drug
                                                                            samples once they are collected?
        development, the proper design of clinical studies intended to
        gather such data, and the implications of these clinical studies
                                                                                                 Ms. Sipes
        for product labeling. The agency has indicated that this internal                        is a Partner in the law firm of
        paper will be developed into an additional guidance document                             Covington & Burling LLP,
        for industry, entitled “Clinical Pharmacogenetic Studies: Study                          Washington, DC.
        Design, Data Analysis and Recommendations For Dosing and
        Labeling,” which may be completed by early next year.3

24       Update    September/October 2008                                                                               
                                                                                                            Personalized Medicine

Consent and Privacy Issues
   Federal regulation
   Testing on human tissue samples is                   Under HIPAA, the release of any
considered “human subject” research by
FDA.5 Any research that involves such
                                                      “protected health information” (PHI)
testing and is intended for submission to              from the study site to the sponsor
FDA must therefore comply with FDA’s
regulations on informed consent and
                                                      requires individual “authorization.”
institutional review board (IRB) review.6
The Health Insurance Portability and
Accountability Act (HIPAA) federal             site to use his study-related data and        ward. To the extent the samples are al-
privacy regulations7 are also generally ap-    disclose that data to the sponsor.9           ready in the sponsor’s possession, further
plicable in the clinical research context.        When blood and tissue samples are          authorization under HIPAA should not
   In structuring consent documents,           collected from clinical trial subjects        be required.12
considerations affecting compliance with       for pharmacogenomic research, those              With regard to informed consent
FDA’s informed consent rules and the           samples are liable to implicate HIPAA         in the use of leftover samples, the key
applicable HIPAA requirements are often        protections for PHI, particularly if the      question is whether the subjects’ original
intertwined. Take for example the com-         samples are identified by a unique code.10    informed consent is broad enough to en-
mon scenario in which a sponsor seeks to       Therefore, the subject must authorize the     compass the additional research. If not,
collect blood samples from clinical trial      use of his/her sample for the sponsor’s       the regulatory picture can be somewhat
participants with the intention of per-        future research. If the subject’s author-     complicated. Where the samples are to be
forming tests on those samples at some         ization to future testing is included         used in research that might eventually be
point in the future. These might be ge-        in the main study consent, however, the       submitted to FDA, informed consent to
netic tests designed to identify individual    document will essentially combine two         that research may be inadequate unless
variations associated with a particular        authorizations in a manner that is incon-     the subjects are reconsented. While the
dose response or a certain adverse event.      sistent with HIPAA requirements.11 In         risk to subjects of such additional testing
In this scenario, where samples are being      practical terms, if the authorization for     on leftover samples is arguably small,
obtained prospectively, consent issues         the main study and the authorization          FDA regulation generally does not allow
are fairly straightforward. The informed       for future testing on the sample are          IRBs to waive informed consent require-
consent documents should be worded to          combined in a single document, the            ments on the basis of minimal risk.13
obtain the subjects’ consent to any future     subject has no way to “opt out” of the           In a 2006 guidance document, FDA’s
testing that the sponsor might perform         tests on his sample if he does not wish to    Center for Devices and Radiologi-
on their samples. If genetic testing is con-   have those tests performed. Some sub-         cal Health (CDRH) indicated that the
templated, that should be made explicit.       jects may, for example, wish to decline       agency would exercise enforcement
   With regard to HIPAA, the issues are        future genetic testing on their samples if    discretion with regard to informed con-
more complex. Under HIPAA, the release         such testing is not necessary to the main     sent requirements where leftover tissue
of any “protected health information”          study. For these reasons, it is generally     samples were used for research related
(PHI) from the study site to the spon-         preferable to obtain the subject’s authori-   to in vitro diagnostic (IVD) devices, pro-
sor requires individual “authorization.”8      zation of future testing on his sample in     vided the specimens were not individu-
Often, the authorization for release of        a separate document.                          ally identifiable.14 While the reasoning in
study-related data to the sponsor is built        A second scenario arises where a spon-     this guidance would appear applicable to
into the informed consent document for         sor is in possession of leftover samples,     research in the drug context as well, the
the main study. As is acknowledged in          or sample remnants, from a completed          Center for Drug Evaluation and Research
the HIPAA regulations, a subject cannot        clinical trial. Can these samples be used     (CDER) has not issued similar guidance,
participate in a clinical study if he does     for additional research? In this scenario,    and a similar exercise of enforcement
not sign an authorization allowing the         the HIPAA issues are fairly straightfor-      discretion by CDER cannot be assumed.

FDLI                                                                                                    September/October 2008   Update    25
     Personalized Medicine

                                                                                                    collected for research purposes, there
                                                                                                    are exceptions. Under Florida law, for
                                                                                                    example, the results of any genetic testing
            Ownership is an issue controlled                                                        are “the exclusive property of the person
         by state law, however, and these cases                                                     tested” and may not be disclosed without
                                                                                                    individual consent.23
            are not necessarily controlling in                                                         Given the lack of clarity on ownership
                    other jurisdictions.                                                            issues, sponsors should not assume that
                                                                                                    subjects enter studies with an ownership
                                                                                                    right in their tissues, or that such rights
                                                                                                    are transferred to the sponsor when the
        In undertaking research on leftover            creates an authorization requirement that    sample is collected. These assumptions
        samples, therefore, sponsors should            is in addition to federal HIPAA regula-      could give rise to an implication that sub-
        think ahead as to whether informed con-        tions. The provision is limited to the use   jects are being asked to waive their legal
        sent to that research will be considered       or disclosure of individually identifiable   rights as part of the informed consent
        adequate. If questions arise about the         information, however, and might not          process, and such waiver is prohibited
        adequacy of informed consent after the         apply to research on samples that bear       under FDA regulation.24 Instead of as-
        research is submitted in a marketing ap-       no “personal identifying information.”20     serting ownership over the samples in
        plication, results can range from a delay      Other state laws create broader privacy      informed consent documents, sponsors
        in processing to rejection of the data.        rights that could be invoked by indi-        should simply obtain the subjects’ agree-
                                                       viduals who object to a manufacturer’s       ment that the collection, handling and
        State Law Issues                               testing of their samples or use of their     use of the samples will be at the spon-
           While the bulk of applicable regulation     test results.21                              sor’s direction. The informed consent
        on consent and privacy issues is at the           In short, sponsors conducting research    should also describe how the samples
        federal level, additional issues can arise     on human samples cannot assume               will be coded and whether they will be
        under state law. A number of states, for       that all bases are covered because FDA       anonymized.25 Subjects do have the right
        example, have laws relating to genetic         regulations are complied with. State laws    to “discontinue participation” in human
        testing that create specific restrictions in   should be carefully examined as well.        subject research at any time,26 but this
        a variety of areas, including the disclo-      Among other considerations, state laws       does not equate to a right to physical
        sure of identifying information about test     are the most likely source of provisions     return of the sample. Instead, procedures
        subjects15 and the permissible                 that could give rise to individual causes    should be in place to allow a subject to
        time periods for retention of tissue and       of action against research sponsors.         request that no further research be per-
        DNA samples.16 These laws may also                                                          formed on his sample, to the extent the
        require additional or more detailed            Who Owns the Samples?                        sample is still identifiable.
        informed consent provisions to create a           This is a very common question, and
        valid consent to genetic testing.17 While      one with no clear answer. The handful        Conclusion
        some of these laws have an exception for       of reported court decisions involving           With the rise of personalized medi-
        anonymous testing, the criteria for what       ownership of tissue samples suggest that     cine, the pharmaceutical industry’s
        constitutes “anonymous” may vary.18            where individuals provide samples with       involvement in the collection and testing
           States may also impose additional           no expectation of future possession or       of human tissue samples is only likely
        privacy restrictions that are not limited      control, those individuals retain no right   to increase. At the same time, the public
        to genetic information. For example,           of ownership in their samples.22 Owner-      is becoming increasingly aware of the
        under California law, a manufacturer           ship is an issue controlled by state law,    wealth of genetic information that can be
        may not “share, sell, use for marketing        however, and these cases are not neces-      derived from a small sample of biological
        or otherwise use” any “medical informa-        sarily controlling in other jurisdictions.   material. One example of this growing
        tion” in its possession without individual     While few states have specific laws gov-     awareness is the success of direct-to-
        authorization.19 This California provision     erning the ownership of tissue samples       consumer genetic testing concerns,

26       Update    September/October 2008                                                                             
                                                                                                                                           Personalized Medicine

which charge thousands of dollars to                       Genomic Data and Sample Coding Categories                18 Compare NY Civ. Rights Law § 79-l(9) (specific
                                                           (Apr. 2008).                                                 consent not required where samples are coded and
create personalized genetic profiles from             2     See FDA Guidance for Industry: Pharmacogenomic              “permanently stripped of identifying information”)
a saliva sample.27 In addition, recent                     Data Submissions (Mar. 2005).                                with NJ Stat. Ann. § 10:5-45(a)(5) (specific consent
                                                      3    See Jennifer C. Smith, FDA Revising Pharmacog-
high-profile disputes such as Washington                                                                                not required for “anonymous research where the
                                                           enomics Paper on Labeling, Samples, THE PINk
                                                                                                                        identity of the subject will not be released”).
University v. Catalona28 — in which a                      SHEET (July 10, 2008).
                                                                                                                    19 CA Civ. Code § 56.10(d).
prominent cancer researcher and his pa-               4    See Peter A. Rittenhouse, Framing DNA Collection in
                                                                                                                    20 See id. § 56.05(g).
                                                           the Clinic, BIOCENTURY (Mar. 31, 2008).
tients were defeated in their attempts to             5    See 21 C.F.R. §§ 50.1, 50.3; 56.101, 56.102.
                                                                                                                    21 See, e.g., Mass. Gen. Laws ch. 214 § 1B (creating “a
                                                                                                                        right against unreasonable, substantial or serious
exercise control over a valuable database             6    21 C.F.R. Parts 50, 56.
                                                      7    45 C.F.R. Parts 160, 164.                                    interference with [an individual’s] privacy”).
of human tissue samples — have given                  8    See generally 45 C.F.R. § 164.508.                       22 See. e.g., Moore v. Regents of the University of Cali-
rise to a “tissue rights” movement whose              9    See id. § 164.508(b)(3), (4).                                fornia, 793 P.2d 479 (CA 1990), cert. denied, 499 U.S.
                                                      10   See id. § 164.514(b).                                        936 (1991); Washington University v. Catalona, 437
advocates seek greater individual control
                                                      11   See id. § 164.508(b)(3), (4).                                F.Supp.2d 985 (E.D. MO 2006), aff’d, 490 F.3d 667
over the use and disposition of biological            12   See id. § 164.508(c)(2)(iii).                                (8th Cir. 2007).
materials and genetic information.29In                13   This is in contrast to the Common Rule, which            23 FL Stat. § 760.40(2).
                                                           governs federally funded research. See 45 C.F.R. §       24 See 21 C.F.R. § 50.20.
this environment, close attention to the                   46.116(d) (allowing IRB waiver of informed               25 See ICH Guidance E15, Definitions for Genomic
legal and regulatory requirements sur-                     consent in certain cases involving “no more than
                                                                                                                        Biomarkers, Pharmacogenomics, Pharmacogenetics,
                                                           minimal risk”).
rounding the collection and testing of                                                                                  Genomic Data and Sample Coding Categories.
                                                      14   Guidance on Informed Consent for In Vitro Diagnos-
human tissue will be critical to protect                                                                            26 21 C.F.R. § 50.25(a)(8).
                                                           tic Device Studies Using Leftover Human Specimens
                                                                                                                    27 See Andrew Pollack, Gene Testing Questioned by
sponsors’ investment in pharmacog-                         That Are Not Individually Identifiable, FDA CDRH/
                                                                                                                        Regulators, N.Y. TIMES (June 26, 2008).
                                                           CBER (Apr. 25, 2006).
enomic research. FDLI                                 15   See, e.g., NJ Stat. Ann. § 10:5-47.                      28 Washington University v. Catalona, 437 F.Supp.2d
                                                      16   See, e.g., NJ Stat. Ann. § 10:5-46(a); NY Civ. Rights        985 (E.D. Mo. 2006), aff’d, 490 F.3d 667
1   See International Conference on Harmonization          Law § 79-l(2)(b), (2)(f), (10).                              (8th Cir. 2007).
    (ICH) Guidance E15, Definitions for Genomic       17   See, e.g., NJ Stat. Ann. § 10:5-45; NY Civ. Rights Law   29 See Rebecca Skloot, Taking The Least of You, N.Y.
    Biomarkers, Pharmacogenomics, Pharmacogenetics,        § 79-l(2); FL Stat. § 760.40.                                Times Magazine (Apr. 16, 2006).

FDLI                                                                                                                                September/October 2008           Update      27

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