          United States Court of Appeals
                        For the First Circuit

Nos. 18-1146, 18-1147

             IN RE: CELEXA AND LEXAPRO MARKETING AND
                    SALES PRACTICES LITIGATION


PAINTERS AND ALLIED TRADES DISTRICT COUNCIL 82 HEALTH CARE FUND;
  DELANA S. KIOSSOVSKI; RENEE RAMIREZ, on behalf of herself and
        all others similarly situated; MARLENE T. LOCONTE,

                        Plaintiffs, Appellants,

 MARTHA PALUMBO, individually and on behalf of all other persons
similarly situated; PETER PALUMBO, individually and on behalf of
          all other persons similarly situated; JAYNE EHRLICH,
      individually and on behalf of all other persons similarly
  situated; ANNA MURRET, individually and on behalf of all other
       persons similarly situated; UNIVERSAL CARE, INC.; ANGELA
 JAECKEL; MELVIN M. FULLMER, on behalf of himself and all others
     similarly situated; NEW MEXICO UFCW UNION'S AND EMPLOYER'S
     HEALTH AND WELFARE TRUST FUND, on behalf of itself and all
    others similarly situated; ALLIED SERVICES DIVISION WELFARE
   FUND, on behalf of itself and all others similarly situated;
        TARA JOHNDROW, individually and on behalf of all others
  similarly situated; BRIAN ANSON, individually and on behalf of
   all others similarly situated; SCOTT A. WILCOX, on behalf of
himself and all others similarly situated; MUNICIPAL REINSURANCE
HEALTH INSURANCE FUND; RANDY MARCUS; BONNIE MARCUS; RUTH DUNHAM;
                       TANYA SHIPPY; JILL POWELL,

                              Plaintiffs,

                                  v.

 FOREST PHARMACEUTICALS, INC.; FOREST LABORATORIES, INC.; FOREST
LABORATORIES, LLC, successor in interest to Forest Laboratories,
                              Inc.,

                        Defendants, Appellees,

              PFIZER, INC.; WARNER LAMBERT COMPANY,
                           Defendants.


          APPEALS FROM THE UNITED STATES DISTRICT COURT
                FOR THE DISTRICT OF MASSACHUSETTS

         [Hon. Nathaniel M. Gorton, U.S. District Judge]


                              Before

                      Howard, Chief Judge,
             Torruella and Kayatta, Circuit Judges.


     R. Brent Wisner, with whom Michael L. Baum, Baum, Hedlund,
Aristei & Goldman, P.C., Christopher L. Coffin, and Pendley, Baudin
& Coffin, LLP were on brief, for appellants.
     Andrew J. Ceresney, with whom Edwin G. Shallert, Kristin D.
Kiehn, J. Robert Abraham, Debevoise & Plimpton LLP, John G.
O'Neill, and Sugarman, Rogers, Barshak & Cohen, P.C. were on brief,
for appellees.


                         January 30, 2019
          KAYATTA,       Circuit Judge.             These consolidated appeals

arise out of two so-called "off-label" prescription-drug-marketing

cases aggregated for pretrial proceedings in the District of

Massachusetts by order of the multidistrict litigation panel.

Plaintiffs claim that the defendants, Forest Pharmaceuticals, Inc.

and Forest Laboratories, Inc. (collectively "Forest"), engaged in

fraud to push their antidepressant drugs on unsuspecting minors

for whom the FDA had not approved the use of these medications.

As we will explain, we reverse the dismissal of the claims brought

by two of the four plaintiffs, and we vacate the denial of

plaintiffs'     motion    to    compel        the    production      of   additional

documents by Forest.      We otherwise affirm the challenged district-

court rulings, including the denial of class certification.

                                         I.

          We    begin    by    summarizing          the   relevant   statutory   and

regulatory framework and by reciting the facts relevant to the

plaintiffs' summary-judgment appeal in the light most favorable to

the plaintiffs.     See Boudreau v. Lussier, 901 F.3d 65, 71 (1st

Cir. 2018).

                                         A.

          The    Federal       Food,   Drug,        and   Cosmetic    Act   ("FDCA")

requires drug manufacturers to obtain approval from the U.S. Food

and Drug Administration ("FDA") before marketing a drug for a

particular medical use.         21 U.S.C. § 355(a); see also Mut. Pharm.

                                       - 3 -
Co., Inc. v. Bartlett, 570 U.S. 472, 476 (2013).                  To secure that

approval, the drug manufacturer must submit to the FDA either a

new-drug    application    ("NDA")        or     a   supplemental          new-drug

application ("sNDA"), and the manufacturer must demonstrate the

drug's efficacy for the indicated use in at least two double-

blind,   randomized-controlled      trials       ("DBRCTs").         See    In   re

Neurontin Mktg. & Sales Practices Litig. (Kaiser), No. 04-cv-

10739-PBS, 2011 WL 3852254, at *5 (D. Mass. Aug. 31, 2011), aff'd,

712 F.3d 21 (1st. Cir. 2013); see generally 21 C.F.R. § 314.105.

The FDCA creates both civil and criminal penalties for drug

manufacturers that promote the use of approved drugs for unapproved

uses (referred to here as "off-label" uses).                      See 21 U.S.C.

§§ 331(d), 333(a), 355(a); Lawton ex rel. United States v. Takeda

Pharm. Co., 842 F.3d 125, 128 n.4 (1st Cir. 2016).                       The FDCA,

however, does not prohibit doctors from prescribing drugs for off-

label uses.   Lawton ex rel. United States, 842 F.3d at 128 n.4.

                                     B.

            Forest   manufactures    and       markets   prescription        drugs,

including   the   antidepressant     medications         Celexa    and    Lexapro.

Celexa and Lexapro are chemically similar selective serotonin

reuptake inhibitors ("SSRIs"), a class of antidepressants that

affect a patient's mood by blocking the reabsorption of the

neurotransmitter serotonin in the brain, Eli Lilly & Co. v. Teva

Pharm. USA, Inc., No. 05-1044, 2005 WL 1635262, at *1 (Fed. Cir.

                                    - 4 -
July 13, 2005).     The FDA approved Celexa and Lexapro for the

treatment of major depressive disorder ("MDD") in adults (i.e.,

individuals aged eighteen or over) in 1998 and 2002, respectively.

Drug manufacturers, including Forest, had difficulty demonstrating

that SSRIs were also effective in treating depression in children

and adolescents. As of 2005, only Fluoxetine -- commercially known

as Prozac -- had gained FDA approval for the treatment of pediatric

depression.   In 2009, the FDA approved Lexapro for the treatment

of depression in adolescents (i.e., individuals of ages twelve

through seventeen).    The FDA has never approved Celexa for any

pediatric use nor has it approved Lexapro as a treatment for

depression in children (i.e., individuals under the age of twelve).

          The record in this case nevertheless strongly suggests

that Forest engaged in a comprehensive off-label marketing scheme

from 1998 through 2009 aimed at fraudulently inducing doctors to

write pediatric prescriptions of Celexa and Lexapro when Forest

had insufficient reason to think that these drugs were effective

for the treatment of depression in children and adolescents.

Plaintiffs have pointed to substantial evidence that Forest sought

to achieve this illicit aim by:     (1) promoting Celexa's efficacy

for the treatment of pediatric depression at medical conferences,

at continuing-medical-education programs, and in press releases;

(2) concealing    negative   clinical    studies   concerning   Celexa's

efficacy and safety; and (3) directly encouraging physicians to

                                 - 5 -
prescribe   Celexa     and   Lexapro    for    the    treatment      of   pediatric

depression.

            For    years,    Forest    nevertheless     denied       that    it   was

engaged   in    the   off-label   promotion      of    these    drugs.       Forest

Laboratories'      Executive    Vice    President,     Dr. Lawrence         Olanoff,

testified before Congress in 2004 that "because the FDA has not

approved pediatric labeling for our products, Forest has always

been scrupulous about not promoting the pediatric use of our

antidepressant drugs, Celexa and Lexapro.             That is the law, and we

follow it."       Publication and Disclosure Issues in Antidepressant

Pediatric      Clinical     Trials:    Hearing   Before        the   Subcomm.     on

Oversight & Investigations of the Comm. on Energy & Commerce, 108th

Cong. 82 (2004) (statement of Dr. Lawrence Olanoff).

            Even before Dr. Olanoff assured Congress of Forest's

scrupulousness, a whistleblower had commenced a qui tam action,

alleging that Forest had violated the False Claims Act ("FCA"), 31

U.S.C. § 3729(a), by fraudulently marketing and promoting Celexa

and Lexapro for the off-label treatment of depression in pediatric

patients.      Complaint, Gobble v. Forest Labs., Inc., No. 03-10395-

NMG (D. Mass. Mar. 4, 2003), ECF No. 1.               The United States later

intervened in that suit, and, in February 2009, the district court

unsealed the United States' complaint.               Order Granting Motion to

Unseal, United States ex rel. Gobble, No. 03-10395-NMG (D. Mass.

Feb. 24, 2009), ECF No. 64.            The evidence belying Dr. Olanoff's

                                       - 6 -
assurances    to   Congress   turned   out     to     be   quite   substantial.

Ultimately, in September 2010, Forest paid a $39 million fine in

connection with pleading guilty to criminal violations of the FDCA

for its off-label promotion of Celexa between 1998 and 2002 and an

additional $149 million to the United States to settle civil claims

that Forest illegally promoted Celexa and Lexapro for pediatric

use in 2002 through 2005.

                                      C.

             Within the following four years, over a dozen consumers

and entities who paid for prescription drugs filed the lawsuits

that led to this appeal.      Initially, four plaintiffs joined in the

notice of appeal.      Only two, Renee Ramirez and the Painters and

Allied Trades District Council 82 Health Care Fund ("Painters")

have presented any argument on appeal.                We refer to these two

collectively    as   "plaintiffs."1         Ramirez    purchased     Celexa   and

Lexapro for her young son from February 2003 through March 2010 on

the   recommendation    of    her   son's    neurologist.          Painters   has

reimbursed its pediatric insureds for off-label prescriptions of

Celexa and Lexapro since early 1999.             Plaintiffs together seek



      1Marlene LoConte and Delena Kiossovski joined in the notice
of appeal but subsequently filed no brief, and the single brief
filed by the other parties contains no argument at all for
questioning the grounds upon which the district court dismissed
the claims of LoConte and Kiossovski.    We therefore deem their
appeal of the judgments against them to be waived. See Vázquez-
Rivera v. Figueroa, 759 F.3d 44, 46-47 (1st Cir. 2014).

                                    - 7 -
recovery under the Racketeer Influenced and Corrupt Organizations

Act ("RICO"), 18 U.S.C. § 1962(c)–(d), the Minnesota Consumer

Fraud Act, Minn. Stat. § 325F.69, and the Minnesota Unfair Trade

Practices Act, Minn. Stat. § 325D.13, and for unjust enrichment.

            In June 2016, the district court denied Painters' motion

to certify two nationwide classes of similarly situated health-

insurance    companies        and   health    plans     that      had   paid    for   or

reimbursed off-label pediatric prescriptions of Celexa or Lexapro.

In re Celexa & Lexapro Mktg. & Sales Practices Litig. (Painters I),

315   F.R.D.     116,   131    (D. Mass.      2016).2        In     rejecting      class

certification,      the   court       reasoned      that   while        Painters      had

satisfied the Rule 23(a) numerosity, commonality, typicality, and

adequacy    requirements,       Painters      had   failed     to      establish   that

common questions of fact or law predominated over individual issues

as required by Rule 23(b)(3).           Id. at 123–31.

            Subsequently, in March 2017, a dispute arose as a result

of    Forest's    apparently        belated    production         of    two    internal

memoranda in advance of a deposition conducted by agreement after

discovery had otherwise closed.                The two documents contained



      2Painters' motion for class certification provided no time
period for the proposed Celexa class. At oral argument, however,
plaintiffs' counsel clarified that plaintiffs only seek to
challenge manufacturer-induced prescriptions for off-label uses
made prior to the FDA's approval of Lexapro for adolescent use in
March 2009. Thus, we construe Painters' appeal in accordance with
this statement.

                                       - 8 -
details regarding a study of Celexa's effectiveness.                        Forest

revealed that it had not sought any responsive documents from its

Clinical    Supply     Group   in    responding       to    Painters'    discovery

requests.    The district court nevertheless denied Painters' motion

to compel Forest's supplemental production of documents from this

group, concluding that any such production would be cumulative.

In    re   Celexa      &   Lexapro    Mktg.       &   Sales    Practices    Litig.

(Painters II), 288 F. Supp. 3d 483, 486–87 (D. Mass. 2018).

             In due course, after deeming discovery complete and

ruling on various interim motions, the district court entered

summary judgment for Forest on plaintiffs' RICO claims, holding

that neither Painters nor Ramirez could demonstrate injury.                     In re

Celexa & Lexapro Mktg. & Sales Practices Litig. (Painters III),

289 F. Supp. 3d 247, 253–56 (D. Mass. 2018).                      The court then

proceeded    to     dismiss    plaintiffs’       state-based     allegations      as

deriving from their noncognizable RICO claims.                    Id. at 258–59.

This appeal by Painters and Ramirez followed.

                                           II.

             Summary judgment is appropriate "if the movant shows

that there is no genuine dispute as to any material fact and the

movant is entitled to judgment as a matter of law."                   Fed. R. Civ.

P. 56(a).         In   granting    summary       judgment     dismissing   all    of

plaintiffs' claims, the district court concluded that plaintiffs

had   no    competent      proof    that    either    Celexa     or   Lexapro    was

                                       - 9 -
ineffective for treating depression in children or adolescents.

We review this conclusion de novo.   Martinez v. Petrenko, 792 F.3d

173, 179 (1st Cir. 2015).

                                A.

          Prevailing on a RICO claim requires proof of an economic

injury.   See 18 U.S.C. § 1964(c) ("Any person injured in his

business or property by reason of a violation of section 1962 of

this chapter may sue therefor.").    Plaintiffs allege injury in the

form of payments made for ineffective drugs.3    The district court

therefore turned its attention to determining whether plaintiffs

had enough evidence to allow a jury to find Celexa and/or Lexapro

ineffective for treating pediatric depression.    See Painters III,

289 F. Supp. 3d at 253–56.    Four clinical trials and the FDA's

2009 approval of Lexapro for adolescents informed the district

court's decision.

          Starting in 1997, Lundbeck -- the developer of Celexa -

- began conducting Study 94404, which focused on Celexa's efficacy

in treating depression in adolescents.    The study produced across-

the-board negative results.   Forest then conducted Study MD-18 in

an attempt to demonstrate Celexa's effectiveness in both children


     3 In its opposition to Forest's motion for summary judgment,
Painters argued that it need not demonstrate that Celexa and
Lexapro are ineffective in treating pediatric depression to
establish RICO injury. The district court rejected this argument
in its order granting Forest's motion, and Painters has not
developed any challenge to that ruling on this appeal.

                              - 10 -
and adolescents.         The efficacy results of MD-18 are difficult to

assess    because     Forest    bungled    the     study:    Some    participants

randomized     into      the   active     treatment     group    were     dispensed

nongeneric, pink tablets in one portion of the trial, potentially

unblinding both the individuals who received these pills and the

researchers     conducting       the      study.       The   MD-18 study         only

demonstrated statistically positive results when these potentially

unblinded participants were included.               Finally, in 2002–2004 and

2005-2007, Forest conducted two additional clinical trials.                   Study

MD-15 examined Lexapro's efficacy in children and adolescents and

achieved negative results.         Study MD-32 set out to test Lexapro's

effectiveness       in     treating      only      adolescents      and    achieved

statistically significant positive results.

             Based upon the results of MD-32 and the Celexa MD-18

study, Forest submitted an sNDA to the FDA in 2008.                  In 2009, the

FDA approved the application, allowing Forest to market Lexapro

for use in adolescents.           Forest did not seek such approval for

Celexa.

             Plaintiffs'       evidence    that     Celexa   and    Lexapro      were

ineffective    for       the   pertinent    indications      consisted      of    the

following:      The FDA has neither approved Celexa for treating

depression in children or adolescents nor has it approved Lexapro

for use in children; Study 94404 demonstrated only a detrimental

effect of Celexa in treating depression in adolescents; Study MD-

                                        - 11 -
18 was corrupted and showed no beneficial effect in children and

adolescents unless the potentially unblinded participants are

included    in    the    results;    and     Study MD-15      produced    uniformly

negative results in testing Lexapro's efficacy in children and

adolescents.      In addition, plaintiffs produced expert testimony

opining that the positive results in MD-32 were not of clinical

significance      and    that   MD-18      should   properly     be   considered      a

negative    trial.       Plaintiffs        also    provided    the    results    of   a

2016 meta-analysis        study     that    found    that     neither   Celexa    nor

Lexapro had any more beneficial effect than a placebo in treating

pediatric depression.

            There is also evidence in the record before us, however,

that cuts the other way.             In September 2002, the FDA accepted

Study MD-18 as a positive trial that would support a determination

of Celexa's effectiveness for the treatment of MDD in adolescent

patients.       And in January 2003, the FDA also stated that MD-18

could be employed to support an application for FDA approval "for

both Celexa and Lexapro, in pediatric patients with [MDD]."                       The

FDA relied in part on these findings in approving Lexapro for the

treatment of depression in adolescents in March 2009.                      Further,

Forest points out that neither Painters nor Prime Therapeutics

("Prime"), Painters' pharmacy-benefits manager, has taken any

effort     to    limit    or    remove      from     its    formulary     pediatric

prescriptions of Celexa and Lexapro.

                                        - 12 -
           This record raises two questions.              First, do the FDA's

various pronouncements or actions close the door on any effort to

convince a jury that either Celexa or Lexapro was ineffective?

Second, to the extent that the FDA's pronouncements and actions

are not preclusive, is the evidence in this case nevertheless

insufficient to support a jury finding of ineffectiveness?

                                       1.

           Forest   claims    that    two     of   our   recent    decisions    --

D'Agostino v. ev3, Inc., 845 F.3d 1 (1st Cir. 2016), and In re

Celexa & Lexapro Mktg. & Sales Practices Litig. (Marcus), 779 F.3d

34 (1st Cir. 2015) -- answer the first question in the affirmative

by deeming FDA approval dispositive.               Even were we to find it

convincing, this argument would not cover all the challenged uses

at issue in this appeal.       The FDA has never approved Celexa for

any of the off-label uses for which Forest promoted it.                  Nor has

it approved Lexapro for the treatment of MDD in children under the

age of twelve.      So Forest's reliance on actual FDA approval to

foreclose a jury determination of inefficacy must be limited to

Forest's marketing of Lexapro for adolescent use and, perhaps as

well, to the question of how to construe MD-18.

           In any event, even as thus limited, we do not find

Forest's   reliance   on     D'Agostino       convincing.         The   claim   in

D'Agostino concerned the sale of medical devices after the FDA had

approved the devices for the uses for which they were sold.

                                     - 13 -
D'Agostino, 845 F.3d at 3, 7–9.         In rejecting a challenge to those

post-approval sales under the False Claims Act based on alleged

pre-approval     fraud   on   the    FDA,     we   reasoned   that   "[t]o   rule

otherwise would be to turn the FCA into a tool with which a jury

of six people could retroactively eliminate the value of FDA

approval   and    effectively       require    that   a   product    largely   be

withdrawn from the market even when the FDA itself sees no reason

to do so."       Id. at 8.    Here, by contrast, plaintiffs challenge

only the promotion of Celexa and Lexapro for uses that were off-

label (i.e., not FDA-approved) at the time Forest promoted and

sold the drugs.4     When Forest is said to have made those marketing

efforts, it could not have pleaded reliance on FDA approval.                   If

a jury were to hold Forest liable for such pre-approval marketing,

it would simply be telling Forest that it should not have marketed

that which Congress under the FDCA does not want it to market:

drugs for unapproved uses.          We therefore see no reason to accord

to Forest the preclusive protection for pre-approval promotion

that FDA approval provided the medical-device manufacturer for

post-approval conduct in D'Agostino.5


     4 Though plaintiffs' complaints do not explicitly limit their
RICO and state-law claims to the period prior to FDA's March 2009
approval of Lexapro, plaintiffs' counsel indicated at oral
argument that plaintiffs do not challenge Forest's post-approval
marketing of Celexa and Lexapro.
     5 For similar reasons, Forest's reliance on Buckman Co. v.
Plaintiffs' Legal Comm., 531 U.S. 341, 348 (2001), in which the
Supreme Court rejected as preempted state fraud-on-the-FDA claims,
                                     - 14 -
          Nor does our opinion in Marcus aid Forest in this case.

In Marcus, we rejected a challenge to a drug label based on

information that was "plainly known to the FDA prior to approving

the label."   779 F.3d at 43.   We made clear in doing so, however,

that we were merely applying the state-law preemption principles

the U.S. Supreme Court laid out in PLIVA, Inc. v. Mensing, 564

U.S. 604 (2011), and Wyeth v. Levine, 555 U.S. 555 (2009).      See

Marcus, 779 F.3d at 40–43 (explaining that a drug manufacturer can

only be held liable under state law for inadequate warning in an

FDA-approved label when the drug manufacturer can, "of its own

volition, . . . strengthen its label in compliance with its state

tort duty" (quoting PLIVA, Inc., 564 U.S. at 624)).         Marcus,

accordingly, is inapposite.

          This is not to say that the FDA's 2009 approval of

Forest's sNDA for Lexapro is irrelevant to this case.     Certainly

the approval and the FDA's reliance on MD-18 provide what many

jurors may view as strong evidence confirming that Lexapro, and

perhaps Celexa as well, have always been efficacious in treating

pediatric depression.    The common law has long recognized that

agency approval of this type is relevant in tort suits.         See

Restatement (Third) of Torts: Prod. Liab. § 4 (Am. Law Inst. 1998)


and its progeny is misplaced. Plaintiffs question the efficacy of
Celexa and Lexapro only for off-label uses; their claims,
accordingly, are not predicated on a fraud-on-the-FDA theory of
liability.

                                - 15 -
("[C]ompliance with an applicable product safety statute . . . is

properly considered in [a product defect case].").   But the common

law also recognizes that such evidence is not always preclusive.

Id. ("[S]uch compliance does not preclude as a matter of law a

finding of product defect.").    And while there are strong reasons

for treating such evidence as preclusive when the challenged sales

are made in reliance on agency approval, those same reasons cut

the other way when the sales are made without approval, and

certainly when made unlawfully, as we must assume they were here.

                                  2.

          Having decided that the FDA's subsequent approval of

Lexapro does not preclude proving that pre-approval uses of these

drugs were ineffective, we turn to addressing whether plaintiffs

may proceed with a claim based on product ineffectiveness when the

evidence of efficacy is conflicting.     This is more or less the

question we left unanswered in Kaiser.   See Kaiser, 712 F.3d at 49

(declining to address what evidentiary standard would be needed to

demonstrate efficacy "if the results of DBRCTs were equivocal" or

"if there were a different mix of DBRCT and non-DBRCT evidence").6


     6  To advance its preferred interpretation of the term
"equivocal" in Kaiser, each party dedicates a significant portion
of its brief to sparring over whether the DBRCT evidence in the
Neurontin cases was, in fact, mixed.    We need not address this
question because, as we explain, Painters' RICO claim survives
summary judgment even though the evidence of inefficacy is mixed.
We note, however, that the DBRCTs in the Neurontin case were not
uniformly negative as Forest would have us believe. Rather, the
                                - 16 -
              Generally        speaking,     "conflicting      evidence"   is   the

hallmark of an issue that calls for factfinding, not summary

judgment.         See, e.g., Adria Int'l Grp. v. Ferre Dev., Inc., 241

F.3d       103,    111   (1st     Cir.     2001)    (finding     summary   judgment

inappropriate         when      evidence     presented    was     "contested    and

contradictory"); see also 10A Charles Alan Wright et al., Federal

Practice and Procedure § 2712 (4th ed. 2018) ("[S]ummary judgment

is not a substitute for the trial of disputed fact issues.").                   We

see no reason to deviate from that general rule merely because the

product marketed illegally is one that was later approved for

lawful sales.7           In short, why should we forgo customary fact-

finding by the jury so as to reward unlawful conduct aimed at

getting children to consume unapproved drugs?

              Forest      also    argues     that    plaintiffs'     evidence    of

ineffectiveness falls short of proving injury because Painters has

not produced "individualized" proof that Celexa or Lexapro was

ineffective        for   any    particular    insured.      By    "individualized"

proof, Forest appears to mean testimony from a patient (or from a


district court noted both positive and negative clinical studies
in reviewing the parties' evidence of Neurontin's efficacy for the
at-issue off-label conditions. See Kaiser, 2011 WL 3852254, at
*34–46 (reviewing mixed DBRCT results).
       7
       Nor is summary judgment for Forest warranted due to the fact
that Painters has not directed the removal of Celexa and Lexapro
for pediatric uses from its drug formulary. As we held in Kaiser,
it is "within the factfinder's province to weigh this evidence."
Kaiser, 712 F.3d at 41.

                                         - 17 -
doctor concerning that patient) that the patient experienced no

beneficial effects from the drug.           While evidence of that type

could be probative, certainly it is not the only way to prove that

a drug is ineffective.     Indeed, given that (1) an ineffective drug

may trigger a placebo effect in a given individual and (2) an

effective drug may not benefit all users, individualized proof

might well be less probative than the type of expert, study-based

testimony that plaintiffs have offered.            In any event, as we

already held, such individualized proof is certainly not required.

See In re Neurontin Mtkg. & Sales Practices Litig. (Harden), 712

F.3d 60, 69 (1st Cir. 2013) ("[W]e reject Pfizer's position that

these    plaintiffs     must    prove   the      individual,      subjective

ineffectiveness    of    each   off-label    prescription    in   order   to

establish injury.       . . .   The Harden plaintiffs have proffered

clinical trial evidence that Neurontin is ineffective . . ., which

is certainly enough to raise a genuine issue of fact on the

effectiveness issue." (citation omitted)); In re Neurontin Mtkg.

& Sales Practices Litig. (Aetna), 712 F.3d 51, 59–60 (1st Cir.

2013).

            In sum, we hold that the FDA's 2009 approval of Lexapro

does not preclude a jury from concluding that the off-label uses

of Celexa and Lexapro at issue in this case were ineffective in

treating pediatric depression.      Moreover, plaintiffs have provided

competent   and   sufficient    evidence    --   through    DBRCTs,   expert

                                  - 18 -
testimony, and peer-reviewed literature -- to raise a genuine issue

of material fact as to the efficacy of these drugs for pediatric

use.   Accordingly, the district court erred in granting summary

judgment for Forest on plaintiffs' RICO and state-law claims on

this basis.

                                B.

          In addition to demonstrating economic injury, a RICO

plaintiff must prove that the defendant's racketeering conduct

caused her injury. 18 U.S.C. § 1964(c); Holmes v. Sec. Inv'r Prot.

Corp., 503 U.S. 258, 268 (1992) (interpreting section 1964(c)'s

language to mean that a RICO plaintiff must show both but-for and

proximate causation to establish standing).      As we have already

noted, physicians can -- and do -- lawfully prescribe prescription

drugs for off-label uses, even though the manufacturer is barred

by law from promoting such prescriptions.       See Lawton ex rel.

United States, 842 F.3d at 128 n.4.    So for any given prescription

in this case, one would reasonably ask whether Forest's efforts to

profit by illegally marketing drugs for pediatric use caused a

particular prescription to be made, or whether, instead, the doctor

wrote a given prescription based on his or her own professional

medical judgment (perhaps reasoning that what works for an adult

patient might also work for a younger patient).

          Forest therefore urges that, even if we disagree with

the district court on the issue of injury/efficacy, we should still

                              - 19 -
affirm the entry of summary judgment due to Painters' lack of proof

of but-for causation.       While the district court did not consider

the issue of causation in its summary-judgment ruling, it did

earlier assay Painters' causation evidence in ruling on Painters'

motion for class certification.         The district court labeled the

proof   so    "insubstantial"   and    "fundamentally   flawed"   "as   to

preclude class certification."        Painters I, 315 F.R.D. at 126–28.

Forest would have us interpret these pronouncements as a finding

that the evidence was insufficient as a matter of law to prove

but-for causation.

             We disagree.   In the first place, it is unclear why the

district court gauged the substantiality or merit of plaintiffs'

proof in the context of a Rule 23 motion.         The central issue in

that context is not whether the method of proof would or could

prevail.     Rather, it is whether the method of proof would apply in

common to all class members.          See, e.g., Tyson Foods, Inc. v.

Bouaphakeo, 136 S. Ct. 1036, 1047 (2016) ("When . . . 'the concern

about the proposed class is not . . . some fatal dissimilarity

but, rather, a fatal similarity -- [an alleged] failure of proof

as to an element of the plaintiffs' cause of action -- courts

should engage that question as a matter of summary judgment, not

class certification.'" (alteration in original) (quoting Richard

A. Nagareda, Class Certification in the Age of Aggregate Proof, 84

N.Y.U. L. Rev. 97, 107 (2009))).

                                  - 20 -
          More substantively, Painters' evidence does not seem

clearly insufficient.       There is ample evidence that Forest spent

money inducing doctors to prescribe its drugs to pediatric patients

and that it would not have done so had the effort not been worth

the   money.         Two     experts,      Dr. Meredith    Rosenthal        and

Dr. Christopher     Baum,   also     opined   that   Forest's    spending    on

promotions in general correlated positively with sales.               As the

district court pointed out, Painters' experts then assumed that

this same approximate correlation applied to off-label promotional

spending and off-label sales.         Painters I, 315 F.R.D. at 127.        The

district court thought this assumption to be a "fundamental flaw"

in the analysis.     Id.    Why, exactly, we are not sure.        After all,

why would Forest, which knew its markets better than anyone, have

spent money on off-label marketing over the long term if it

generated lower returns than would additional spending on less

risky, lawful marketing?       Certainly there is room for reasonable

disagreement   on    the    merits    of   Dr. Rosenthal   and    Dr. Baum's

assumption.

          If the jury accepts this assumption as reasonable, and

if it finds that the prescriptions that Painters paid for were

typical of those that the experts analyzed, jurors would then have

a fair path to finding that Forest's off-label marketing caused

Painters to pay for ineffective drugs. The experts' interpretation

of the data indicated that Forest's off-label promotions caused

                                     - 21 -
76% and 54% of all pediatric prescriptions of Celexa and Lexapro,

respectively.     Dr. Rosenthal estimated that if Painters paid for

as few as five independent prescriptions, there would be a 98%

chance that at least one was the result of off-label marketing.

In    fact,   Painters   likely   paid     for   the   Celexa   or   Lexapro

prescriptions of more than five different patients.8            So the odds

that Painters was not harmed if the drugs were, indeed, ineffective

was    likely   infinitesimal     (assuming      the   prescriptions   were

independent of one another).9




      8In its summary judgment order, the district judge observed
that Painters reimbursed sixteen of its pediatric insureds for
seventy-two off-label prescriptions of Celexa from 1999 through
2004, and thirty-one of its pediatric insureds for 234 off-label
prescriptions of Lexapro from 2002 through early 2015. Painters
III, 289 F. Supp. 3d at 251. It is not clear from the record how
many of these Lexapro prescriptions were written prior to March
2009.   Viewing this evidence in the light most favorable to
Painters, Ellis v. Fidelity Mgmt. Tr. Co., 883 F.3d 1, 3, (1st
Cir. 2018), and without any counter-argument on this point by
Forest, we assume for purposes of this appeal only that well more
than five of the aforementioned Lexapro prescriptions were filled
prior to the FDA's 2009 approval of Lexapro.
      9The statistical proof in this instance is being used only
to prove that a group of prescriptions likely includes at least
one that a certain activity caused, and it is then being utilized
to   estimate   the   percentage   of   such   causally   connected
prescriptions in that group.     Painters proposes no use of the
statistical data to prove that Forest's off-label marketing caused
any particular prescription to be written.       See In re Asacol
Antitrust Litig. (Asacol), 907 F.3d 42, 54 (1st Cir. 2018) (finding
it "far from self-evident" that expert testimony opining that
"ninety percent of class members were injured" would be "sufficient
to prove that any given individual class member was injured").

                                  - 22 -
          Nor is Painters' evidence limited to the thrust of its

statistics.    Painters     also    has     evidence   that   Forest   sales

representatives called or visited at least two physicians who

subsequently ordered pediatric prescriptions of Celexa and Lexapro

that Painters reimbursed.    In addition, Painters produced evidence

suggesting that Forest specifically targeted Painters' pharmacy-

benefits manager, Prime, and that Prime relied upon a misleading

report by Forest of Study MD-18 in managing Painters' formulary.

All together, this is surely enough to raise a triable issue of

fact as to whether Forest's off-label marketing caused Painters to

pay for a prescription for which it would not have otherwise paid.

          This is not to say that Painters will ultimately prevail

on the issue of causation.     The district court has not conducted

a Daubert analysis.     And there may be other potential bones to

pick with the sufficiency of Painters' proof of causation.             As the

record now stands, though, we agree with Painters that we cannot

affirm the summary judgment finding that its causation proof is

insufficient as a matter of law.

          As for Ramirez, Forest did not challenge her standing on

the basis of causation in its memorandum in support of its motion

for summary judgment.     Accordingly, we express no opinion as to

whether Ramirez has raised a triable issue on RICO causation.            See

Rosaura Bldg. Corp. v. Municipality of Mayagüez, 778 F.3d 55, 63



                                   - 23 -
(1st Cir. 2015) ("Time and time again we have held that arguments

not advanced before the district court are waived.").

             As for proximate causation, it is of no moment that

pediatricians were the immediate target of Forest's fraudulent

marketing.     Here, as in Kaiser, a jury could find that Painters

and Ramirez were "the primary and intended victims of [Forest's]

scheme to defraud."       Kaiser, 712 F.3d at 37 (quoting Bridge v.

Phx. Bond & Indem. Co., 553 U.S. 639, 650 (2008)).                     Moreover,

Painters'    and    Ramirez's   alleged        harm     (i.e.,   reimbursing   or

purchasing more pediatric prescriptions than they otherwise would

have) was a "foreseeable and natural consequence" of Forest's

scheme.     Bridge, 553 U.S. at 658.           Indeed, it was precisely the

point.

             Accordingly, for the foregoing reasons, we reverse the

district court's entry of summary judgment for Forest on Painters'

RICO and state-law claims and on Ramirez's RICO and unjust-

enrichment claims.

                                       III.

             Early on in this litigation the district court denied

Painters' motion to certify this case as a class action under

Federal Rule of Civil Procedure 23(b)(3).                     In so ruling, the

district    court   reasoned    that    a     variety    of   important   issues,

including causation and injury, would pose individual questions

that would need to be answered for each class member.               Painters I,

                                   - 24 -
315 F.R.D. at 123–30.        The presence of these individual questions,

reasoned the district court, defeated Painters' effort to satisfy

the     requirement     of   Rule 23(b)(3)      that     common   issues   must

predominate.      Id.   Painters now appeals that ruling as it applies

to classes consisting of third-party payors ("TPP") who paid for

or reimbursed prescriptions of Celexa or Lexapro prior to early

2009.    It is not clear why those issues to which the district court

pointed would preclude certification of such a class.               As we have

already explained, Painters' clinical and statistical evidence, if

believed, could establish causation and injury at least for any

TPP who paid for more than a handful of different patients'

prescriptions.        Nevertheless, as we will explain, it has become

apparent that the proper application of the statute of limitations,

while     preserving     plaintiffs'        individual    claims,    precludes

Painters' attempt to maintain a class action.

                                       A.

            The    parties     agree   that     the    applicable    statutory

limitations period is four years.             See Agency Holding Corp. v.

Malley-Duff & Assocs., Inc., 483 U.S. 143, 156 (1987).              That four-

year period began to run "at the time [the] plaintiff knew or

should have known of his injury."             Lares Grp., II v. Tobin, 221

F.3d 41, 44 (1st Cir. 2000) (citing Rodriguez v. Banco Central,

917 F.2d 664, 665 (1st Cir. 1990)).          The injury here is the payment

made on account of off-label prescriptions that Forest induced.

                                    - 25 -
See Kaiser, 712 F.3d at 39 ("[E]conomic injury occur[s] when

[plaintiff] paid for fraudulently induced [drug] prescriptions.").

So, the key question becomes:         By what date can we say, as a matter

of law, that Painters knew or should have known that Forest was

promoting the off-label, ineffective use of Celexa or Lexapro?

             The district court found that date to be no later than

March of 2009.       In re Celexa & Lexapro Mktg. & Sales Practices

Litig., 65 F. Supp. 3d 283, 289 (D. Mass. 2014).             In February of

that year, the United States unsealed its complaint against Forest

in United States ex rel. Gobble, which detailed in thirty-three

pages how "Forest engaged in a fraudulent scheme to market and

promote   Celexa . . .       and   Lexapro . . .      off-label      to   treat

depression     and   other    psychiatric       conditions      in    pediatric

patients."    Complaint at 2, United States ex rel. Gobble, No. 03-

10395-NMG (D. Mass. Feb. 13, 2009), ECF No. 61 [hereinafter United

States'   Complaint].        Within    weeks,   two   private    class-action

complaints followed, one in New York and another in Missouri, each

also alleging a fraudulent scheme to market Celexa and Lexapro for

ineffective,     off-label    uses.       See   Class   Action       Complaint,

Universal Care, Inc. v. Forest Pharm., Inc., No. 09-cv-11518-NMG

(D. Mass. Mar. 20, 2009), ECF No. 1; Class Action Complaint, N.M.

UFCW Union's & Emp'rs' Health & Welfare Tr. Fund v. Forest Labs.,

Inc., No. 09-cv-11524-NMG (D. Mass. Mar. 12, 2009), ECF No. 1.

Painters never argued before the district court that it was unaware

                                   - 26 -
of the United States' complaint or the March 2009 lawsuits.                    Nor

does it so argue on appeal.             Rather, it argues that the lawsuits

did not provide enough notice that Forest had been promoting the

off-label use of Celexa and Lexapro.               Such notice, Painters says,

was not available until Forest's own public admission to that

effect in November 2010, when it both pleaded guilty to criminal

violations    of   the    FDCA    and    entered    into   a    civil   settlement

agreement with the United States.

           Not surprisingly, Painters points to no case law holding

that a statutory limitations period does not start to run until

the potential defendant first delivers a gift-wrapped admission of

its alleged wrongdoing.          Were that the rule, very few limitations

periods would ever commence, much less conclude.                  Instead, as we

have explained in an analogous context, "[w]e look first to whether

sufficient facts were available to provoke a reasonable person in

the    plaintiff's       circumstances       to     inquire      or     investigate

further.     . . .       Once a duty to inquire is established, the

plaintiff is charged with the knowledge of what he or she would

have   uncovered     through     a   reasonably      diligent    investigation."

McIntyre v. United States, 367 F.3d 38, 52 (1st Cir. 2004); see

also Sanchez v. United States, 740 F.3d 47, 52 (1st Cir. 2014)

("The discovery rule incorporates an objective standard.                   To delay

commencement of the running of the statute of limitations, 'the

factual basis for the cause of action must have been inherently

                                        - 27 -
unknowable, [that is, not capable of detection through the exercise

of reasonable diligence] at the time of injury.'" (alteration in

original) (quoting Gonzalez v. United States, 284 F.3d 281, 288–

89 (1st Cir. 2002))).          The same fundamental principle applies to

RICO suits.          See Rotella v. Wood, 528 U.S. 549, 555 (2000)

("Federal courts . . . generally apply a discovery accrual rule

when a statute is silent on the issue, as civil RICO is here.             . . .

[D]iscovery     of    the     injury . . .   is    what   starts   the   clock."

(citations omitted)); Koch v. Christie's Int'l PLC, 699 F.3d 141,

150–51 (2d Cir. 2012) (noting that a RICO claim does not accrue

until a plaintiff has "actual or inquiry notice of the injury"

(quoting In re Merrill Lynch Ltd. P'ships Litig., 154 F.3d 56, 60

(2d Cir. 1998))).

            We agree with the district court that the unsealing of

the United States' complaint and the subsequent lawsuits filed in

March 2009 were more than sufficient to put a TPP like Painters on

notice   that        Forest     had    likely     been    inducing    off-label

prescriptions of Celexa and Lexapro.            The United States' complaint

chronicled how Forest suppressed a negative study on Celexa while

promoting   a   positive       study   (which     conveniently     neglected   to

mention the earlier, negative study).             United States' Complaint at

3, 14.   The complaint quoted internal Forest communications and

recounted the precise details of Forest's unlawful promotional

activities. Id. at 15–22. It quoted Forest's physician-call notes

                                       - 28 -
reporting on the efforts of Forest's sales representatives to

promote the pediatric use of the drugs.         E.g., id. at 20 ("[F]ocus

on   Lexapro     efficacy    at   just     10 mg.,     great   choice   for

child/adolescents.").       It also named Forest marketing executives,

e.g., id. at 23, and outside physicians involved in the promotion

campaigns, e.g., id. at 21–22.          It is inconceivable that any TPP

like Painters would not have found in the complaint a very strong

probability that Forest had systematically and fraudulently pushed

its drugs on unsuspecting children.

           Nevertheless, we also agree with the district court that

Painters survived Forest's statute-of-limitations defense because

the running of the limitations period was stayed for more than

eight months by the filing of the N.M. UFCW class action in March

2009.   See In re Celexa & Lexapro Mktg. & Sales Practices Litig.,

65 F. Supp. 3d at 291.      Painters was a member of the putative RICO

class   action    for   which     the    N.M.   UFCW    complaint    sought

certification.     Under American Pipe & Construction Co. v. Utah,

414 U.S. 538 (1974), the limitations period during which Painters

might sue on its own behalf was therefore tolled until the N.M.

UFCW class action was dismissed in June 2010. Forest did not cross

appeal the district court's application of American Pipe.           Rather,

Forest argues only that the limitations period began running long

before March of 2009 when plaintiffs first should have suspected

that Celexa and Lexapro were ineffective for pediatric use.              We

                                  - 29 -
reject   that   argument    because   the       injury   here   is   paying      for

unlawfully induced off-label prescriptions, not merely physician-

directed, off-label prescriptions.

                                      B.

           Even though plaintiffs can sue, thanks to American Pipe,

Painters cannot parlay that dispensation into the much-delayed

filing of a class action.         See China Agritech, Inc. v. Resh, 138

S. Ct. 1800 (2018).    In American Pipe, the Supreme Court held that

the "commencement of [a putative class action] tolls the running

of the statute for all purported members of the class who make

timely motions to intervene after the court has found the suit

inappropriate for class action status." 414 U.S. at 552-53. China

Agritech clarified that this tolling rule has limits:                     While a

putative   class   member   may    join    an    existing   suit     or   file    an

individual action upon denial of class certification, a putative

class member may not commence a class action anew beyond the time

allowed by the untolled statute of limitations.                 138 S. Ct. at

1807 ("The 'efficiency and economy of litigation' that support

tolling of individual claims do not support maintenance of untimely

successive class actions; any additional class filings should be

made early on, soon after the commencement of the first action

seeking class certification." (citation omitted) (quoting Am.

Pipe, 414 U.S. at 553)).



                                   - 30 -
          Painters argues that China Agritech is distinguishable

from the case at hand because there was no substantive ruling on

class certification in N.M. UFCW; the first time any district court

addressed class certification was in Painters' case.       Painters'

position relies on an impermissibly narrow reading of the Court's

decision in China Agritech.     Though the Supreme Court granted

certiorari in that case to answer the narrow question of whether

a putative class member may commence a class action beyond the

limitations period upon the district court's denial of a request

for class certification filed within the statute of limitations,

id. at 1804, the Court proceeded to provide a broader answer:   Its

precedents do not "so much as hint[] that [American Pipe] tolling

extends to otherwise time-barred class claims," id. at 1806. Thus,

the Court effectively ruled that the tolling effect of a motion to

certify a class applies only to individual claims, no matter how

the motion is ultimately resolved.     To hold otherwise would be to

allow a chain of withdrawn class-action suits to extend the

limitations period forever.

          For the foregoing reasons, the district court did not

abuse its discretion in declining to certify Painters' proposed

nationwide class of TPPs.

                               IV.

          Finally, Painters also takes issue with the district

court's denial of its motion to compel Forest's supplemental

                              - 31 -
production of documents related to the MD-18 Study.                    This court

reviews   a      district    court's    discovery   decision     for    abuse   of

discretion, intervening "only upon a clear showing of manifest

injustice, that is, where the lower court's discovery order was

plainly   wrong      and    resulted    in   substantial   prejudice      to    the

aggrieved party."           Pina v. Children's Place, 740 F.3d 785, 791

(1st Cir. 2014) (quoting Dennis v. Osram Sylvania, Inc., 549 F.3d

851, 859 (1st Cir. 2008)).

              Here, it is undisputed that Forest did not perform an

exhaustive search in response to Painters' requests for documents

related     to    the      MD-18 Study:       Indeed,   Forest    acknowledges

(employing the passive voice) that "files within the custody of

the Clinical Supply Group were not searched."               Forest also does

not deny that its own preliminary search within this group -- after

discovery      had   closed     --    produced   two    responsive      memoranda

regarding the packaging error in the MD-18 Study.              The only excuse

Forest provides is that "[p]laintiffs were fully apprised of the

scope of document collection and were aware that files within the

custody of the Clinical Supply Group were not searched."                  Forest,

however, points us to nothing in the record demonstrating that

Painters acquiesced to Forest's limiting the scope of its document

collection in this way.              These admissions notwithstanding, the

district court denied Painters' Rule 37 motion to compel the

supplementary production of documents related to the MD-18 Study.

                                       - 32 -
It reasoned that the Rule 26(e)(1) duty to supplement only applies

when "the supplemental material has not been otherwise made known

to the requesting party" and observed that Painters had already

received   "substantial     production    of   documents   related    to   the

packaging error" such that any new production would be cumulative.

Painters II, 288 F. Supp. 3d at 487.

           Rule 26(e)(1) requires that a party who has responded to

a request for production supplement its response in a timely manner

"if the party learns that in some material respect the . . .

response   is    incomplete . . .        and   if   the    additional . . .

information has not otherwise been made known to the other parties

during the discovery process."       Fed. R. Civ. P. 26(e)(1).        Whether

or not "information has not otherwise been made known" -- and,

thus, whether or not additional production would be cumulative --

necessarily hinges on the relevance that the additional production

might have for the requesting party's claims and the complexity of

the issue that the factfinder is tasked to resolve; clearly, a

relatively high degree of granularity in document production is to

be expected in technical matters of great significance to a party's

overall claim.

           The   district    court   viewed     FDA   approval   as     being

preclusive as to the validity of Studies MD-18 and MD-32.                  See

Painters III, 289 F. Supp. 3d at 255–56.              It also viewed the

validity of those two studies as fatal to plaintiffs' attempt to

                                  - 33 -
prove ineffectiveness with the type of evidence used in Neurontin.

See id.        Given those views, the district court understandably

decided that further evidence on the question of effectiveness was

cumulative and of no material import.              See Painters II, 288 F.

Supp. 3d at 487.         Because we have now explained why the FDA's

approval of Lexapro for its use in adolescents is not as preclusive

as the district court might have reasonably thought, and because

Painters and Ramirez have a live claim on the merits, one might

reasonably expect Forest to search for responsive files within the

"Clinical Supply Group."            Accordingly, we vacate the district

court's discovery ruling so that on remand it can consider whether

further discovery is called for in view of our decision in this

appeal.

                               V.    Conclusion

             For   the   foregoing    reasons,    we   reverse   the   district

court's entry of summary judgment for Forest on Painters' and

Ramirez's RICO and state-law claims and vacate the district court's

denial    of    Painters'   Rule 37     motion    to    compel   supplemental

discovery. At the same time, we affirm the district court's denial

of Painters' motion for class certification.            We award no costs to

any party.




                                     - 34 -
