How Forest Misled the FDA, DOJ, USAO, and the Public about the Results of Celexa Study MD-18

January 24, 2018

Gregg Shapiro, Esq.

Chief of the Affirmative Civil Enforcement Unit
United States Attorney’s Office
District of Massachusetts
1 Courthouse Way, Suite 9200
Boston, MA 02210

Re. How Forest Misled the FDA, DOJ, USAO, and the Public about the Results of Celexa Study MD-18

Dear Mr. Shapiro:

On September 15, 2010, Forest Laboratories, Inc. and Forest Pharmaceuticals, Inc. (“Forest”) entered into a series of agreements with the United States Attorney’s Office for the District of Massachusetts (“USAO”).

First, Forest agreed to plead guilty to one count of obstruction and two counts of distributing a misbranded drug under the Food, Drug, and Cosmetic Act. The third count specifically related to Forest promoting the use of the antidepressant Celexa (citalopram) for use in children and adolescents between 1998 and 2002. The plea agreement imposed criminal fines of $39,500,000 for Celexa’s off-label promotion. Second, Forest entered into a civil settlement agreement to resolve various qui tam False Claims Act lawsuits. The settlement resolved, in part, allegations of fraudulent off-label promotion for both Celexa and Lexapro (escitalopram) for children and adolescents between 1998 and 2005. Forest agreed to pay $149,158,057.66 to settle these claims. Third, Forest entered into a corporate integrity agreement to address Forest’s promotional conduct for a period lasting five years. Each agreement was contingent on the others and each agreement required complete honesty from Forest.

We have been litigating various cases against Forest related to the off-label promotion of Celexa and Lexapro for pediatric use for some years now—inspired by the USAO’s original investigation—in a multidistrict litigation proceeding in the District of Massachusetts. Over the past several years, our litigation has revealed that the scope and extent of Forest’s fraud was not honestly disclosed to the USAO (or, to the Food and Drug Administration) and that Forest misrepresented material facts underlying the USAO’s prosecution. Documents and testimony obtained in our litigation have been unsealed, over Forest’s objection, and we have prepared a 2 detailed memorandum outlining Forest’s misconduct and fraud with the hope the USAO will consider reopening its investigation. Obviously, we are not an unbiased source of information, however, we believe the documents and testimony speak for themselves.

For example, a central feature of Forest’s wrongful conduct, which formed the basis of the government’s investigation, involved the promotion and dissemination of a “positive” Celexa double-blind, placebo-controlled clinical trial in children and adolescents, MD-18, and the suppression of a negative Celexa double-blind, placebo-controlled clinical trial in adolescents, Study 94404. However, unsealed documents and testimony show that the “positive” MD-18 study was not actually positive, and that Forest misled the FDA, the USAO, and the public about this fact. Specifically, MD-18 was only able to achieve a positive result by including nine patients in the study that were, as Forest’s medical director put it, “automatically unblinded” due to a dispensing error. In fact, when the mishap occurred, Forest told the FDA that it would exclude these patients from the primary results. However, when Forest learned it needed the unblinded patients to achieve a positive result, i.e., to show that Celexa outperformed a sugar pill, Forest snuck the patients back into the results, and falsely told the FDA the patients were not actually unblinded.

One internal document, in particular, reveals that this was deliberate fraud. Amy Rubin, a Forest Regulatory Affairs Manager, characterized the dispensing error as having “the potential to cause patient bias” in a draft letter to be sent to the FDA to disclose the unblinding problem. Dr. Charles Flicker, the Senior Medical Director overseeing MD-18, did not approve of this language, stating: “Altho ‘potential to cause bias’ is a masterful stroke of euphemism, I would be a little more up front about the fact that the integrity of the blind was unmistakenly [sic] violated.” Ms. Rubin responded: “Thanks for the compliement [sic]. Part of my job is to create ‘masterful’ euphemisms to protect Medical and Marketing.” Thus, not only was the disclosure to the FDA dishonest, it was, according to a Forest Regulatory Affairs manager, her job to mislead the FDA and protect medical and marketing.

This “masterful euphemism” language was ultimately sent to the FDA. When we deposed Dr. Thomas Laughren, the former official at the FDA who reviewed this study and who, within six months after leaving the FDA, was working as a testifying expert for Forest, he testified that he believed at the time he reviewed the study that there had been no unblinding and, when shown our documents and testimony, that Forest did not honesty disclose the situation to him.

The gravity of this misconduct becomes even more acute when one considers that Lexapro
was ultimately approved by the FDA for adolescent depression in 2009 based on the supposedly
“positive” results of MD-18. Dr. Laughren personally approved the new indication for Lexapro
and testified that, if MD-18 was negative, he would not have approved it. It is our understanding
that this approval weighed heavily into the USAO’s decision to settle their case against Forest.

We urge you to review the enclosed memorandum and accompanying evidence and consider
reopening your investigation of Forest related to its promotion of Celexa and Lexapro for
pediatric use. We would be happy to answer any questions you may have or to meet you in
person to walk you through the evidence.


Sincerely,
BAUM HEDLUND ARISTEI & GOLDMAN, P.C.
By:_________________________________
R. Brent Wisner

MEMORANDUM

How Forest Misled the FDA, USAO, and the Public about the Results of Celexa Study MD-18

January 24, 2018

By:
R. Brent Wisner, Esq.
[email protected]
Michael L. Baum, Esq.
[email protected]
BAUM, HEDLUND, ARISTEI & GOLDMAN, P.C.
12100 Wilshire Blvd., Ste 950
Los Angeles, CA 90049
(310) 207-3233

TABLE OF CONTENTS

PART I. EXECUTIVE SUMMARY ............................................................................................. 3

PART II: CELEXA PEDIATRIC CLINICAL TRIALS ............................................................. 10

Celexa Study 94404 Was a Negative Clinical Trial ............................................. 10

Table 1 – Celexa Study 94404 Efficacy Results ................................................... 10

Celexa Study MD-18 Was a Negative Clinical Trial, but Forest Misled the FDA

about the Results ................................................................................................... 12

Table 2 – Celexa Study MD-18 Efficacy Results ................................................. 12

A. General Overview of MD-18 Study .......................................................... 13

B. At the Beginning of the Trial, a Packaging Error Caused Nine Patients,

and their Investigators, to Become Unblinded .......................................... 15

Celexa Study Dispensing Diagram ....................................................................... 18

C. Forest Knowingly Misled the FDA about the Nature of the Unblinding by

Using, As Forest Regulatory Affairs Manager Put It, “Masterful

Euphemisms” to “Protect Medical and Marketing”.................................. 19

D. Despite Misrepresenting the Unblinding to the FDA, Forest Promised to

Exclude the Data from the Patients from Its Primary Efficacy Analysis . 21

E. Forest Reneged on its Promise to Exclude the Unblinded Patients from the

Primary Efficacy Results and, Again, Misrepresented the Unblinding in

MD-18’s Final Study Report .................................................................... 22

F. The FDA Never Fully Considered the Unblinding Issue and a Reasonable

Regulator at the FDA Could Review this New Information and Conclude

Study MD-18 Was Negative ..................................................................... 28

G. Forest Also Misled the FDA about the Results of the Secondary Endpoints

................................................................................................................... 32

Table 3 – Comparison of MD-18 Study Report & Dr. Heart Medical Review .... 35

PART III: FOREST USED FALSE RESULTS FROM MD-18 TO PROMOTE PEDIATRIC

USE OF CELEXA AND LEXAPRO ........................................................................................... 36

PART IV: THE LEXAPRO PEDIATRIC TRIALS .................................................................... 42

Lexapro Study MD-15 Was a Negative Clinical Trial ......................................... 42

Table 4 – Lexapro Study MD-15 Efficacy Results ............................................... 42

Lexapro Study MD-32 Was a “Positive” Clinical Trial for Adolescents, but Did

Not Show a Meaningful Difference between Lexapro and Placebo ..................... 42

PART V: FOREST LEVERAGED THE FALSE RESULTS OF MD-18 TO OBTAIN AN

ADOLESCENT INDICATION FOR LEXAPRO........................................................................ 45

PART VI: FOREST USED THE FALSE ASSERTION THAT MD-18 WAS POSITIVE AND

THE FDA’S APPROVAL FOR LEXAPRO TO NEGOTIATE REDUCED PENALTIES IN

USAO CASE ................................................................................................................................ 53

PART I. EXECUTIVE SUMMARY

In 2010, the USAO in the District of Massachusetts entered into a series of agreements with
Forest Laboratories, Inc. and Forest Pharmaceuticals, Inc., (“Forest”) relating, in part, to the off-label
(unapproved) promotion of Celexa (citalopram) and Lexapro (escitalopram) for use in
children and adolescents.1 Forest agreed to plead guilty to engaging in a misdemeanor count of
off-label promotion for Celexa between 1998 and 2002 and pay $39 million in fines.2
Additionally, Forest entered into a civil settlement agreement to resolve, in part, allegations that
Forest fraudulently induced false claims for the pediatric use of Celexa and Lexapro to be
submitted to government healthcare payers between 1998 and 2005.3 Forest agreed to pay $149
million to settle these claims.4 Forest also entered into a Corporate Integrity Agreement (“CIA”)
designed to monitor the promotional practices of Forest for a period of five years.5 The Plea
Agreement, Civil Settlement, and CIA were conditioned on each other6 and required that Forest
be honest with the USAO about its conduct.7

A central feature of Forest’s wrongful conduct involved the promotion and dissemination of
a “positive” Celexa double-blind, placebo-controlled clinical trial in children and adolescents,
MD-18, and the suppression of a negative Celexa double-blind, placebo-controlled clinical trial
in adolescents, Study 94404. Forest’s one-sided presentation of the efficacy data raised concerns
about how companies such as Forest disclose and use data collected during clinical trials,
particularly when used as part of an off-label promotion campaign. Indeed, the factual claim of
one “positive” trial and one “negative” trial played an important role in the USAO’s prosecution
of the original case against Forest.

Recently unsealed documents and testimony, however, show that Celexa Study MD-18 was
not a “positive study” and that Forest misled the FDA, the USAO, and the public about this fact.
In other words, a material fact that formed the basis of the USAO’s and Forest’s negotiations
was, at that time, false, and Forest knew it. Moreover, this misconduct does not stop there.
Shortly before the USAO and Forest finalized their agreements, the FDA approved Lexapro for use in adolescents, based in part on the misrepresented MD-18 (Celexa) study. The fact that
Forest obtained FDA approval for Lexapro for use in adolescents militated against the
government’s prosecution. The 2009 Lexapro approval, however, was based on the false claim
that MD-18 was positive—a false assertion made to the FDA in 2002 (and reasserted to the FDA
in 2008 as part of Forest’s supplemental New Drug Application (“sNDA”) for Lexapro). If MD-
18 had properly been disclosed as negative, the FDA would not have approved Lexapro for use
in adolescents8 and the government’s prosecution of Forest would have included Forest’s
misrepresentations regarding Celexa’s efficacy in two studies—not just the suppression of Study
94404.

The issue centers on how Forest manipulated the MD-18 data to obtain a “positive” result.
All of the secondary endpoints for MD-18 were negative, meaning Celexa did not outperform
placebo in treating depression on all four of the pre-specified secondary endpoints.9 Moreover,
of those patients who completed the study, i.e., the observed cases, there was also no statistical
difference between Celexa and placebo.10 However, Forest represented to the FDA, USAO, and
others that the primary endpoint for MD-18 was positive because, although the difference was
very small, Celexa appeared to outperform placebo to a statistically significant degree. It turns
out, however, that this “positive” result was based on data from nine patients who were
unblinded during the study. When the data from these unblinded patients is removed, however,
the primary result is negative—indeed, the results are negative across the board on every primary
and secondary endpoint.11

How did this happen? At the beginning of the clinical trial, two clinical investigators
informed Forest that some of their patients were receiving pink pills and others were receiving
white pills.12 This prompted an investigation by Forest, which discovered that a packaging error
had caused the medication for the patients randomized to the Celexa group to be pink, Forest-
stamped, dose-stamped, oval-shaped, commercial Celexa tablets.13 Forest immediately notified
the clinical investigators that the pink pills were commercial Celexa and instructed them to
replace the medication with properly blinded white pills.14 However, for the nine patients
already randomized to the trial, Forest directed the clinical investigators to continue the patients
with the wrong-colored pills.15 This meant the first nine patients were unblinded—the
investigators knew the patients taking the pink pills were taking Celexa and the patients taking
white pills were on placebo.

In March 2000, after Forest learned of the dispensing error but before the results of the study
were known, Forest drafted a letter to send to the FDA explaining the situation. In the original
draft, Forest stated that the dispensing error could have “unblinded the study.”16 However,
Forest’s regulatory affairs manager, Amy Rubin, changed the letter to state that the dispensing
error had the “potential to cause patient bias.”17 This prompted Forest’s medical director, Dr.
Charles Flicker, to respond: “Altho ‘potential to cause bias’ is a masterful stroke of
euphemism, I would be a little more up front about the fact that the integrity of the blind was
unmistakenly violated.”18 Un-phased by Dr. Flicker’s concern that Forest was not being “up
front” with the FDA, Ms. Rubin responded: “Thanks for the compliement [sic]. Part of my job
is to create ‘masterful’ euphemisms to protect Medical and Marketing.”19 For Ms. Rubin,
misleading the FDA was not only acceptable, it was part of her job. And, she did her job well.
The letter sent to the FDA in March 2000 used the masterful euphemism language.20

The letter did, however, state that “[f]or reporting purposes, the primary efficacy analysis
will exclude the . . . potentially unblinded patients[.]”21 Thus, before Forest had the results of
MD-18, Forest recognized the data was corrupted and promised that “[a] full complement of 160
patients” would still be “enrolled under standard double-blind conditions.”22
The results for MD-18 were revealed to Forest in August 2001 and Forest learned, for the
first time, that if the nine unblinded patients were excluded from the analysis, as it had promised
the FDA it would do, the results would be negative.23 But, Forest reneged on its promise to the
FDA. When it submitted the final study report to the FDA in April 2002, Forest included the
unblinded patients in the primary efficacy analysis and buried, in an appendix, the results of the
primary efficacy analysis excluding the unblinded patients.24 In the narrative section of the
report, Forest explained that there had been a dispensing error where nine patients received pink-
colored pills, but the patients “were otherwise blinded.”25 This is in stark contrast to Dr.
Flicker’s unequivocal pronouncement that the integrity of the blind was unmistakenly violated.
In its submission to the FDA, Forest did not disclose that the investigators were unblinded or that
the medication dispensed was Forest-branded, dose-stamped, oval-shaped commercial Celexa
tablets. When the FDA reviewed the results of MD-18, it copied and pasted the language from
the final study report and parroted the claim that pink pills were dispensed but were “otherwise
blinded.”26 Forest’s deception worked—the FDA had no idea that the nine patients were actually
unblinded27 and that the study, when properly analyzed, was negative across the board.

Before the MD-18 study report was even written or given to the FDA, Forest started
promoting the “positive” results of MD-18 to physicians. Forest issued a press release
emphasizing the importance of the positive MD-18 study in a field, i.e., SSRI treatment of
pediatric depression, which had consistently failed to produce positive results28; paid Dr. Karen
Wagner (an investigator on the study) to present the false “positive” results of the study at
various academic conferences and, directly, to physicians in CME programs and in-person offlabel
promotion meetings29; and published the false results of MD-18 in a ghostwritten manuscript and then instructed its sales force to use the publication to promote the use of Celexa
and Lexapro in children.30 None of these presentations and publications disclosed the unblinding
issue. It was buried.

The impact of the off-label promotion of the false data was known to Forest, as demonstrated
in the following slide taken from Forest’s internal marketing plan31 discussing its anticipated
launch of Lexapro:

When Forest’s off-label promotion was finally exposed by the USAO in 2010 and Forest was
forced to settle and plead guilty to the crime, Forest did not disclose its fraud related to MD-18.
Instead, Forest represented to the USAO and DOJ that MD-18 was positive, militating its
misconduct in suppressing the dissemination of Study 94404. Thus, Forest’s false assertion that
MD-18 was a positive study formed, in part, the basis of the USAO’s negotiated settlements with
Forest. These documents and testimony clearly demonstrate that Forest made material
misrepresentations to the USAO and FDA about this issue and, in fact, continues to do so to this
very day. When Dr. William Heydorn was deposed, the former Forest scientist responsible for
preparing the MD-18 final study report and a named author on MD-18’s publication with Dr.
Wagner, he admitted “I wish we had done things a little differently . . . probably should have
been more forthcoming[.]”32

_____________

1 See Exh. 1, DOJ Press Release.
2 Exh. 2, Plea Agreement at 5; see Exh. 3, Criminal Information ¶¶ 55-71 (outlining allegations);
Exh. 5, Side Letter Agreement with Forest Laboratories.
3 Exh. 4, Civil Settlement Agreement at pp.3-4, ¶¶ G(1)-G(3). While the settlement
encompassed the years 1998-2005, there is evidence that Forest’s sales representatives were
illegally off-label promoting Celexa and Lexapro through 2009. One of Forest’s marketing
executives testified: “I have knowledge that representatives may have presented Celexa or
Lexapro inappropriately” and, when asked, “Between 2002 and 2009?” the marketing executive
replied: “Yes.” Exh. 7 Azari Depo at 236:1-237:22.
4 Id. at pp. 6, ¶ 1.
5 Exh. 6, Corporate Integrity Agreement.
6 Exh. 2, Plea Agreement at pp. 11; Exh. 4, Civil Settlement Agreement at pp.3 ¶ E, pp. 10 ¶ 5;
Exh. 6, Corporate Integrity Agreement at 1.
7 Exh. 2, Plea Agreement at pp. 6; Exh. 4, Civil Settlement Agreement at pp.17 ¶ 15.
8 See Exh. 8, 2017 Depo. of T. Laughren at 401:15-402:10 (Dr. Thomas Laughren, the senior
FDA official who approved Lexapro for use in adolescents admitting that he would not have
approved Lexapro for adolescents if MD-18 was negative).
9 Exh. 9, Excerpts of Study MD-18 Rpt. at pgs. 101-104, 244.
10 Id. at 111 (listing p-value of observed cases analysis at week at as 0.1670); Exh. 8, 2017 Depo.
of T. Laughren at 97:1-21, 99:18-21, 343:6-10 (“Q. Sure. But we know that the OC results for
the people who actually completed the clinical trial, that actually was negative for efficacy,
right? A. That’s true.”); Exh. 11, 2016 Depo. of W. Heydorn at 138:24-139:6, 144:6-9.
11 Exh. 12, 2016 Depo. of S. Closter (Forest’s Rule 30(b)(6) Corporate Representative) at
294:10-295:20 (“If they were removed from the study, I understand that the result would have
been negative.”).
12 See Exh. 13, Draft FDA Letter with C. Flicker Handwritten Comments at 1 (describing how
Forest learned of the dispensing error).
13 Id.; see Exh. 14, Memo re. Investigation of CIT-MD-18 Clinical Study Use of Trade-Dress
Citalopram 20 mgs Tabs at 1-2; Exh. 15, Memo re. CIT-MD-18 (Deviation Report) at 1-2 (“It
was brought to our attention . . . some patients enrolled in this study had pink tablets in their bottles. We immediately investigated . . . We discovered . . . the pink oval tablets with FP/20MG
imprints.”).
14 Exh. 16, Email re. CIT-18 FAX to Investigational sites (w/ attachment) at 1 (“[A] copy of the
FAX that went out to all CIT-MD-18 Pediatric Investigational sites this morning is attached[.]”).
15 Id. at 2 (directing patients already randomized to continue on with study).
16 Exh. 17, Email re. Letter to FDA for CIT-18 (w/attachment) at 2 (“The purpose of this letter is
to inform the agency that due to a clinical supplies packaging error for the above-referenced trial,
eight randomized patients at two investigational sites were dispensed medication that could have
potentially unblinded the study.”).
17 Exh. 18, Email responses re. Letter to FDA for CIT-18 at 1.
18 Id.
19 Id.
20 Exh. 19, Letter from T. Varner (Forest) to R. Katz (FDA) at 1.
21 Id.
22 Id.
23 See Exh. 20, Email re. CIT-MD-18 at 1 (“We need to generate Tables 4.1A and 4.1B for ITT
population, excluding the 9 patients who were unblinded at the beginning of the study. Can you
please tell Qiong who they are and try to get the results before 9:30, Friday morning?”).
24 See Exh. 21, Email re. Notes from conference call Oct 4 (w/attachment) at 2 (“[S]ome
citalopram table[t]s were not blinded. The 9 patients who received unblinded medication were
included in the main analyses; a secondary ‘Post-hoc analysis of the ITT subpopulation’ was
done. Refer to these analyses briefly in methods and results and reference the reader to the
appendix table.”); Exh. 9, Excerpts of Study MD-18 Rpt. at pgs. 70, 244 (unblinded results).
25 Id. at pg. 44.
26 Exh. 22, Review and Evaluation of Clinical Data by Dr. Earl Hearst, FDA at 11. All but two
words of Dr. Hearst’s medical review of MD-18 were copied and pasted from the final study
report.
27 Exh. 8, 2017 Depo. of T. Laughren at 154:6-23 (“18 Q Okay. So it was your understanding
that the patients, despite receiving different color tablets, were still blinded, correct? . . . THE
WITNESS: Well, that -- that was -- that was my assumption, correct.”).
28 Exh. 23, 2001 Forest Press Release at 2-3 (“This study is significant because few studies
involving any antidepressant have shown efficacy compared to placebo in the treatment of
depression in children and adolescents . . . Citalopram is now one of the few therapies for which
we have data showing safety and efficacy for this population.” (quoting Dr. Karen Wagner)).
29 Exh. 24, Email re. Ped data at 2 (“[W]e would like to wrap some PR and CME around this
data”); Exh. 25, Email re. ACNP pediatrics abstract at 1 (“John wants GCI to start working a
release and any other way they can spin this data.”); Exh. 26, Emails re. ACCAP meeting at 1 (“You should discuss with GCI bringing her [Dr. Wagner] in for media training prior to the start
of the CME program.”); Exh. 27, Emails re. ACCAP Meeting at 3 (“We spoke with Karen
Wagner today about the current state of affairs regarding the pediatric data. . . She . . . reminded
us that if we want to appeal to the PCP and Pediatric audiences, we need to publish in a place
that provided the appropriate readership . . . She also said that the lack of data regarding the use
of Celexa for pediatrics is limiting it to ‘last choice’ among physicians - she just wanted to make
sure we understood the marketing advantages of the data.”).
30 See, e.g., Exh. 28, Selection of Call Notes at 7, 16-17 (“discussed cx used in children . . . and
results of dr wagner study regarding cx use for children and adolescents . . . Brought up the
Wagner study and sent study to Dr. asked Dr if it would make a difference to use Lx in that age
group since Cx has done well.”).
31 Exh. 29, Lexapro Tactical Presentation at pg. 12; see also id. at pgs. 10-14 (discussing
strategies to increase under 20 market).
32 Exh. 11, 2016 Depo. of W. Heydorn at 307:24-308:15.

PART I: THE PLACEBO EFFECT AND STUDYING ANTIDEPRESSANT EFFICACY

All drugs are susceptible to the placebo effect—the effect a drug has on a patient that has
nothing to do with the medicinal properties of the drug but is caused by the very act of getting
medical attention.33 The belief that one is possibly experiencing medical treatment, by itself, can
create significant and measurable improvement for many conditions.34

In 1962, reeling from news of birth defects caused by a drug called thalidomide, Congress
amended the Food Drug and Cosmetic Act (the Kefauver Harris Amendment, Pub. L. No. 87-
781, 76 Stat. 780 (1962)). Before a drug could be sold as an effective medication, the drug
maker would be required to prove the drug could outperform placebo or, in other words,
demonstrate that the benefit patients receive from a drug could not simply be duplicated by
administration of placebo.35

Today, a drug’s efficacy is determined using double-blind randomized controlled trials
(“DBRCTs”).36 A DBRCT involves the systematic comparison of patients taking a drug and
patients taking a placebo.37 Patients enrolled in the clinical trials are randomly assigned into two
groups. One group takes the drug and the other takes a placebo. However, neither the
investigators nor the patient know which group each patient is in. Once the study is complete,
the benefit observed in the two groups is compared, and if the patients taking the drug
meaningfully outperform the patients in the placebo group, the clinical trial is considered
positive.38 If the drug does not outperform placebo, it is called negative.

As its name suggests, a DBRCT involves three elements, all of which are designed to limit
bias: (1) double-blind (2) randomized (3) controlled trials.39 First, the trial must be double-blind.
This means neither the investigator nor the patient know whether the pill ingested by the patient
is the active drug or placebo.40 If either the investigator or the patient is unblinded, it invalidates
the data since there is no way to determine whether the effects observed are caused by the drug
or caused by the placebo effect (for the patient and investigator). Second, the trial must be
randomized.41 Patients assigned to the drug or control group must be randomly assigned.
Otherwise, the distribution of patients would, itself, inject bias into the study. Finally, the trial
must be controlled. This means the drug must be compared to a control group, i.e., a placebo
pill.42

Before a DBRCT is conducted, a study protocol is generated.43 The protocol specifies the
study’s endpoints—the primary and secondary measures that determine whether the drug
works—and the conduct / procedures of the study. In nearly all DBRCTs, before a study will be
considered positive, the primary endpoint must statistically outperform placebo. This means that
the difference between the drug and placebo must be large enough to conclude the difference
was not a result of chance. Conventionally, and for the purposes of the DBRCTs discussed in
this memorandum, to be considered statistically significant, the endpoint must have a p-value (a
statistical measure) less than 0.05.44

_____________

33 Exh. 30, U.S. Food and Drug Administration (FDA), Guidance for Industry, E 10 Choice of
Control Group and Related Issues in Clinical Trials, at 4 (May 2001).
34 Id.
35 See 21 C.F.R. § 314.126.
36 In re Neurontin Mktg. & Sales Practices Litig., 712 F.3d 21, 47-49 (1st Cir. 2013).
37 See FDA, supra note 33, at 4-5.
38 Id. at 5.
39 Exh. 31, Food and Drug Administration (FDA), Guidance for Industry, E9 Statistical
Principles for Clinical Trials, at 10-14 (Sept. 1998).
40 Id. at 10 (“Blinding or masking is intended to limit the occurrence of conscious and
unconscious bias in the conduct and interpretation of a clinical trial arising from the influence
that the knowledge of treatment may have on the recruitment and allocation of subjects, their
subsequent care, the attitudes of subjects to the treatments, the assessment of end-points, the
handling of withdrawals, the exclusion of data from analysis, and so on.”); see FDA, supra note
33, at 4 (listing possible ways bias enters a trial without blinding). In the context of clinical trials
related to depression, this factor is particularly important where a patient’s depression is assessed
by an investigator based on the patient’s answers to specified questions about how they feel. If
either the investigator or the patient knows they are receiving the drug, that knowledge will
likely influence their assessment.
41 FDA, supra note 39, at 12 (“In combination with blinding, randomization helps to avoid
possible bias in the selection and allocation of subjects arising from the predictability of
treatment assignments.”).
42 Id. at 18.
43 Id. at 3 (“For each clinical trial contributing to a marketing application, all important details of
its design and conduct and the principal features of its proposed statistical analysis should be
clearly specified in a protocol written before the trial begins.”). The protocol must be followed
religiously. See Exh. 32, Ravindra B. Ghooi, et al., Assessment and classification of protocol
deviations, 7 PERSPECTIVES CLIN. RES. 3, 132-36 (July-Sept. 2016) (discussing importance of
following protocols and how deviating from them can lead to misleading study results); Exh. 33,
Stephen L. George & Marc Buyse, Data fraud in clinical trials, 5 CLIN. INVEST, 2 161-173
(2015) (discussing how falsification of data, i.e., misrepresenting important events in a clinical
trial, are the most egregious types of misconduct).
44 Exh. 34, Food and Drug Administration (FDA), DRAFT Guidance for Industry, Multiple
Endpoints in Clinical Trials, at 4-5 (Jan. 2017) (discussing the typical use of a p-value of less
than 0.05).

PART II: CELEXA PEDIATRIC CLINICAL TRIALS

There were two pediatric trials conducted on Celexa: Study 94404 and MD-18. And, as
discussed below, both were negative for efficacy on every primary and secondary endpoint.

I. Celexa Study 94404 Was a Negative Clinical Trial

Celexa Study 94404 was conducted in Europe by Forest’s partner, Lundbeck, and was
submitted to the FDA on March 21, 2002.45 The study involved 244 depressed adolescents, aged
13-18.46 The study had one primary endpoint and nine secondary endpoints.47 As illustrated in
Table 1, all endpoints were negative.

Table 1

Forest learned that Study 94404 was negative on July 16, 2001.49 This was approximately
around the time Forest also learned about the results of MD-18. Forest made a deliberate
decision to suppress the results of 94404 while promoting the results of MD-18.50 Dr. William
Heydorn, a former Senior Medical Writer at Forest, explained:

Q. Were you aware of anyone at Forest Labs who shared the view that it would
be best if the positive data of CIT-MD-18 Was in the marketplace before the
negative data of 94404 was out in the marketplace?
. . .
A. Yes.
. . .
Q. And who did you understand to share that view?
A. I think most of the individuals associated with the citalopram project held that
view.
. . .
Q. Was it your understanding at the time that you were working at Forest Labs
that positive data would be better than negative data in terms of marketing
Celexa?
. . .
A. Yes.
Q. And that positive data being put out in the marketplace over negative data
would be better for the sales of Celexa?
. . .
A. I certainly wasn’t in the sales and marketing department, but that would be my
understanding, yes.51

The investigators at Lundbeck were eager to get the results of 94404 published, but Forest
and Lundbeck wanted to make sure the “positive” results of MD-18 were in the public domain.52
Thus, for three years, the results of Study 94404 remained concealed. Then, in 2004, the New
York Times published an article criticizing Forest for publishing MD-18 without mentioning the
negative results of Study 94404.53 This prompted an immediate response from Forest where it
issued a press release disclosing the results of Study 94404.54 Study 94404, however, did not get
published until 2006—five years after Forest and Lundbeck obtained the results.55

II. Celexa Study MD-18 Was a Negative Clinical Trial, but Forest Misled the FDA
about the Results

Celexa Study MD-18 was conducted by Forest in the United States. It involved 174 pediatric
patients diagnosed with depression, aged 7-17.56 The final study report for MD-18 was
submitted to the FDA on April 8, 2002.57 MD-18 had one primary and four secondary
endpoints.58 As illustrated in Table 2, all five endpoints were negative. For those patients who
actually completed MD-18, i.e., “observed cases,” the results were also negative (p-value of
0.167).59

Table 2

In any DBRCT, data collected from the patients must be double-blind. The protocol for MD-
18 stated that: “Any patient for whom the blind has been broken will immediately be discontinued
from the study and no further efficacy evaluations will be performed.”61 Dr. William Heydorn,
the primary author of the final study report for MD-18,62 confirmed that, pursuant to the
protocol, unblinded patients were to be excluded from any efficacy analysis.63 And, this makes
sense. Efficacy in a depression trial is based on an investigator’s subjective assessment of a
patient’s subjective responses to questions on a depression questionnaire. If either the patient or
investigator knows whether the patient is taking a real drug or a placebo, it could very well
influence the patient’s answers and the investigator’s subjective scoring. Indeed, the FDA has
identified multiple types of bias associated with blinding:

  • Subjects on active drug might report more favorable outcomes because they
    expect a benefit or might be more likely to stay in a study if they knew they
    were on active drug.
  • Observers might be less likely to identify and report treatment responses in a
    no-treatment group or might be more sensitive to a favorable outcome or
    adverse event in patients receiving active drug.
  • Knowledge of treatment assignment could affect vigor of attempts to obtain
    on-study or follow-up data.
  • Knowledge of treatment assignment could affect decisions about whether a
    subject should remain on treatment or receive concomitant medications or
    other ancillary therapy.
  • Knowledge of treatment assignment could affect decisions as to whether a
    given subject’s results should be included in an analysis.
  • Knowledge of treatment assignment could affect choice of statistical analysis.

Blinding is intended to ensure that subjective assessments and decisions are not

affected by knowledge of treatment assignment.64

Forest told the FDA, DOJ, and USAO that MD-18 was a positive study because, even though
all of the secondary endpoints were negative (as well as the observed cases analysis), Forest
claimed the primary endpoint reached statistical significance. This, however, was untrue. As
discussed in detail below, the first nine patients randomized into MD-18 were unblinded because
of a packaging error. Under the protocol, these initial nine patients should not have been
included in the efficacy analysis. And, without these patients included, MD-18 was negative on
every endpoint, including the primary endpoint. Internal documents and the testimony of former
employees demonstrate that Forest deliberately misled the FDA about the extent of the
unblinding and that MD-18, when properly assessed, is negative.

A. General Overview of MD-18 Study

Dr. Paul Tiseo, Joan Barton, and Dr. Charles Flicker oversaw MD-18.65 Dr. Tiseo was the
Medical Monitor for MD-18, Ms. Barton was the Clinical Trial Manager of MD-18, and Dr.
Flicker was Dr. Tiseo and Ms. Barton’s supervisor, overseeing all of the clinical trial programs
related to Celexa and Lexapro.66 Dr. Tiseo was responsible for the overall conduct of the
study.67 Above Dr. Flicker was Dr. Ivan Gergel and, above him, was Dr. Lawrence Olanoff.68
After MD-18 was completed, Dr. Tiseo left Forest, and Dr. William Heydorn took responsibility
for drafting and publishing the results of MD-18 in both the final study report and subsequent
academic publication.69

When a child was enrolled in the study, the child and their parent were dispensed medication
at different pre-specified intervals as reflected below:

Visit 1 Week -1 Patient dispensed 1 bottle containing 10 placebo pills.
Visit 2 Week 0 Patient randomized. Dispensed 1 bottle containing 10 pills.
Visit 3 Week 1 Patient dispensed 1 bottle containing 10 pills.
Visit 4 Week 2 Patient dispensed 2 bottles containing 10 pills.
Visit 5 Week 4 Patient dispensed 1 bottle containing 40 pills.
Visit 6 Week 6 Patient dispensed 1 bottle containing 40 pills.
Visit 7 Week 8 Study completed.70

At Visit 1 (week -1), each patient was put through a one-week placebo screening period, also
known as a placebo run-in.71 During this period, the patient was given one week of medication
in a 10-pill bottle containing placebo pills.72 This period was single-blinded—meaning the
patient did not know the pills were placebo, only the investigator knew.73

At Visit 2 (week 0), patients were assessed to see how they responded to the 1 week placeboscreening
period.74 If they responded, they were not allowed to enter the randomized portion of
the trial.75 The remaining patients were randomized into either the placebo or Celexa group. At
this point, each patient’s baseline was established.76 The randomization was supposed to be
double-blind, meaning neither the patient nor the investigator knew which group the patient was
assigned to. Each patient was given another 10-pill bottle containing either blinded-placebo or
blinded-Celexa.77

At Visit 3 (week 1), the investigator conducted another round of assessments to see how, if at
all, the patient was responding to treatment.78 As part of this process, each patient was required
to return unused medication and the investigator was required to count the number of remaining
pills in the bottle to ensure compliance.79 At the end of the visit, the patients were dispensed a
new 10-pill bottle to last until the next visit, the following week.80

At Visit 4 (week 2), like at Visit 3, more assessments were done and the pills were counted.
The patients were then dispensed two 10-pill bottles to last the next two weeks.81

At Visit 5 (week 4), the patients were given another round of assessments and the pills were
counted.82 At this half-way point in the trial, the investigators were permitted to increase the
patient’s dose by double if the patient was not responding.83 If so, the patient was expected to
take two pills instead of one each day.84 Accordingly, at Visit 5 (week 4), each patient was given
a 40-pill bottle, which would last two weeks until the next visit.85

At Visit 6 (week 6), more assessments and pill counts were conducted and the patients were
dispensed another 40-pill bottle to last two more weeks.86

At Visit 7 (week 8) the study was completed and the final assessments were performed. The
success of each patient was determined by a comparison of the patient’s improvement (or lack of
improvement) between Visit 2 (week 0) and Visit 7 (week 8).87

B. At the Beginning of the Trial, a Packaging Error Caused Nine Patients, and their
Investigators, to Become Unblinded

Shortly after MD-18 began enrolling patients, Forest learned of a packaging error.
According to Dr. Tiseo, two “investigational sites called in to report that some of their patients
were receiving white tablets and others were receiving pink tablets.”88 Forest investigated and,
“it was discovered that a number of bottles of ‘active’ medication were mistakenly packed with
the pink-colored commercial Celexa® tablets instead of the standard white citalopram tablets
used for blinded clinical studies.”89

According to an investigation by the clinical supply group within Forest, the 10-pill bottles to
be used in the Celexa group did not contain the standard white blinded pills, but contained pink,
oval-shaped, Forest-branded, and dose-stamped commercial Celexa® tablets.90 See photo below.

To correct the packaging error, Dr. Tiseo ensured “all sites were notified of this error by
telephone and by fax.”91 In the fax, Dr. Tiseo informed each investigational site about the
packaging error and told each site that the pink pills they were seeing in the patients already
randomized were “pink-colored commercial Celexa® tablets instead of the standard white
citalopram tablets used for blinded clinical studies.”92 Dr. Tiseo explained that “dispensing these
tablets would automatically unblind the study.”93 Dr. Tiseo instructed each investigational site
to immediately return the unblinded medication for repackaging.94 However, for those patients
already randomized, i.e., already receiving the commercial Celexa tablets, Dr. Tiseo instructed
each site to keep using the unblinded medication.95

The problem, however, is that for those patients already randomized into the study, the
patients and the investigators were unblinded. The investigators brought the packaging error to
Forest’s attention because some patients were receiving white pills and some were receiving pink
ones. When Dr. Tiseo told investigators the pink pills were commercial Celexa tablets, even if
the patients somehow did not know the Forest-branded tablets were the active drug, the
investigators knew the patients getting the pink pills were getting Celexa and the patients getting
white pills were getting inert placebos. Dr. Flicker admitted this during his deposition: “[I]f an
investigator were to look . . . at returned medication and he saw that the tablets were pink . . .
then I would think the investigator would be able to draw the conclusion that the patient was on
active drug.”96 Dr. Heydorn also conceded: “If an investigator knows which patients are taking
branded Celexa and which ones are taking white pills, doesn’t that mean the integrity of the blind
was . . . unmistakenly compromised? . . . It does raise questions about the integrity of the blind,
yes.”97

Additionally, there is strong evidence that the patients randomized into the Celexa group
were also, individually, unblinded. First, the average improvement of the blinded patients in the
study taking Celexa was 21.3 points on the CDRS scale.98 However, the average improvement
for the unblinded patients given commercial Celexa for the first four weeks was 30.5 points.99
This 50% greater improvement in the unblinded Celexa patients, versus the blinded Celexa
patients, is strong evidence that those patients or investigators were, in fact, unblinded.

Second, the patients in the Celexa group who were given the commercial Celexa tablets
would have been exposed to different color and shaped pills throughout the trial. Specifically,
the pink tablets were only located in the 10 pill bottles, which were only dispensed during the
four weeks after randomization. The last four weeks of trial used the 40-pill bottles, which
contained the standard, blinded, white pills. However, prior to being randomized, every patient
was given white placebo pills during the one week placebo run-in period. So, this means, these
patients would have been given white pills for one week, pink commercial Celexa pills for four
weeks, then white placebo-looking pills for four weeks.100 This is illustrated in the diagram on
the next page.101

Diagram

According to the protocol for MD-18, “[a]ny patient for whom the blind has been broken will
immediately be discontinued from the study and no further efficacy evaluations will be
performed.”102 This means any unblinded patients should have been excluded from the study
efficacy evaluations. Dr. Heydorn confirmed this fact: “[P]er the protocol, those patients should
have been excluded because they were unblinded, correct? . . . Yes.”103

Internal Forest documents confirm these patients were, in fact, considered unblinded by the
Forest scientists and statisticians working on MD-18. For example, Ms. Barton sent an email to
Drs. Tiseo and Flicker on December 6, 2000, inquiring about whether MD-18 would need to
have additional patients enrolled due to the fact “the study drug was unblinded.”104 In another
email, dated August 10, 2001, Jane Wu, a biostatistician working on MD-18, explained they
needed to generate tables “excluding the 9 patients who were unblinded at the beginning of the
study.”105 In another email, dated April 5, 2002, Julie Kilbane was finalizing the submission of
MD-18 and sent an email explaining that “[s]ome of the supplies were unblinded for this
study[.]”106 Within Forest, there was no ambiguity about whether these patients were actually
“unblinded.”

C. Forest Knowingly Misled the FDA about the Nature of the Unblinding by Using, As
Forest Regulatory Affairs Manager Put It, “Masterful Euphemisms” to “Protect
Medical and Marketing”

After correcting the packaging error to prevent further “automatic” unblinding, Forest
debated whether to notify the FDA of the problem. Dr. Tiseo drafted an initial version of a letter
to send to the FDA.107 Dr. Flicker reviewed it and advised not sending any letter, but, if Forest
did send a letter, he advised giving considerably less detail.108 After incorporating Dr. Flicker’s
comments, Dr. Tiseo circulated a draft version of the letter to various Forest executives and
regulatory personnel, including Lawrence Olanoff, Ivan Gergel, Amy Rubin, Tracey Varner,
Julie Kilbane, and Dr. Flicker.109 The draft letter stated that the dispensed medication could have
“unblinded the study.”110 Dr. Tiseo solicited comments from the group.111

Amy Rubin, who worked in Regulatory Affairs, edited the letter, changing the language from
stating that the dispensing error could have “unblinded the study” to stating the error had the
“potential to cause patient bias.”112 Ms. Rubin’s edit drew criticism from Dr. Flicker who felt
Ms. Rubin’s edits were not up front: “Altho ‘potential to cause bias’ is a masterful stroke of
euphemism, I would be a little more up front about the fact that the integrity of the blind was
unmistakenly violated.”113 This criticism, however, did not prompt Ms. Rubin to correct the
language of the letter. Instead, Ms. Rubin responded: “Thanks for the compliement [sic]. Part
of my job is to create ‘masterful’ euphemisms to protect Medical and Marketing.”114 For Ms.
Rubin, misleading the FDA was not only acceptable, it was part of her job.115

And, she did her job well. The letter ultimately sent to the FDA on March 20, 2000,
contained the misleading “masterful euphemism” language.116 The letter did not disclose that the
patients dispensed the pink pills were “automatically unblinded” as Dr. Tiseo stated to the
investigators or that, as Dr. Flicker noted, the integrity of the blind was “unmistakenly violated.”
The smokescreen was up.

As part of the MDL litigation, Plaintiffs deposed Dr. Thomas Laughren, the former Director
of Psychiatric Drug Products in the Division of Neuropharmacological Drug Products at the
FDA. He personally reviewed the final study report for MD-18 while at the FDA and,
ultimately, was the man at the FDA who approved Lexapro for use in adolescents in 2009.117 Dr.
Laughren departed the FDA in 2013 and, within months, was working as a testifying expert for
various pharmaceutical companies, including Forest.118 In fact, Dr. Laughren was hired as a
testifying expert for Forest to provide opinions about the pediatric efficacy of Celexa and
Lexapro and whether the drugs can increase the risk of suicidal behavior in children.119
Notwithstanding Dr. Laughren’s unseemly transition from regulating Forest at the FDA to
working for Forest, he was shown the euphemism emails and other documents, and he took
offense to Forest’s conduct:

[Q]. [D]oes it concern you that the clinical medical director at the time, Dr.
Flicker, believes that a letter that is being proposed to the FDA contains “a
masterful stroke of euphemism”?
[A]. Yeah, no, that’s – that’s concerning, I would say. . . .

[Q.] Does it concern you that an employee for Forest whose job it is to interact
with the FDA states that it’s part of her job to “create masterful
euphemisms to protect medical and marketing”?
[A]. It -- it is objectionable. I mean, my -- my expectation of -- of companies
is that they will be, you know, completely transparent with -- with the
FDA about what happened in the conduct of a trial.
. . .
[Q.] Does it concern you that Ms. Rubin, whose job it was to interact with the
FDA, believes that it’s her job to “create masterful euphemisms to protect
medical and marketing”? . . .
[A.] What -- what concerns me is -- is that -- you know, what was represented
to FDA was not precisely what happened.120

D. Despite Misrepresenting the Unblinding to the FDA, Forest Promised to Exclude the Data from the Patients from Its Primary Efficacy Analysis

While the March 20, 2000 letter to the FDA misrepresented the nature of the unblinding to
the FDA, it also stated: “For reporting purposes, the primary efficacy analysis will exclude the
eight potentially unblinded patients, with a secondary analysis including also to be
conducted.”121 This sentence was added by Dr. Flicker to the original draft of the letter.122 Dr.
Flicker, consistent with his view that the integrity of the blind was unmistakenly violated, knew
the data from these patients was corrupted. So, Forest promised the FDA, consistent with the
express wording of the MD-18 study protocol, that the unblinded patients would not be counted
in the primary efficacy analysis and that, instead, “[a] full complement of 160 patients will be
enrolled under standard double-blind conditions.”123 Dr. Flicker acknowledged: “[Y]ou were
suggesting that the nine patients subject to the dispensing error were not standardly doubleblinded,
correct? . . . I think it does suggest that.”124 Importantly, this promise to exclude the
unblinded patients from the primary efficacy analysis was made before Forest knew the results of
the primary efficacy endpoint turned on the inclusion of those patients.

E. Forest Reneged on its Promise to Exclude the Unblinded Patients from the Primary
Efficacy Results and, Again, Misrepresented the Unblinding in MD-18’s Final Study
Report

The protocol for MD-18 only required the enrollment of 160 patients.125 However,
accounting for the unblinded patients, the study would need to randomize at least 169 patients
total so that Forest would have a full-complement of patients under standard double-blind
conditions. Forest ultimately randomized 174 patients into the study, including nine of the
unblinded patients.126 So, for purposes of powering the study with sufficient patients, MD-18
did not require the data from the unbinded patients.127

After the MD-18 data was collected, however, Forest reneged on its promise to exclude the
unblinded patients from the primary efficacy analysis. Without any consultation with the FDA,
Forest slipped the unblinded patients into the primary efficacy analysis—combining the data
from the unblinded patients with the blinded cohort—and prepared a secondary “post-hoc”
analysis excluding the patients and put it in an appendix.128 Including these unblinded patients
into the results was “substantial.”129 With the unblinded patients in the study, the primary
endpoint reached statistical significance, but with the unblinded patients excluded—as Forest
promised the FDA—all primary and secondary endpoints were negative. Had Forest done what
it promised, the study would have been negative. In fact, Forest’s corporate representative
conceded that MD-18 is a negative study when the unblinded patients are excluded.130 So did
Dr. Heydorn, the primary author of the MD-18 study report:

Q. By excluding these nine patients, the P-value went from a statistically
significant .038 to a statistically insignificant .052 on the CDRS-R rating
scale after 8 weeks, correct?
[A]. Yes.

Q. So, in other words, this P-value shows citalopram versus placebo was
negative for the primary outcome measure for MD-18, right?
[A]. Yes.131

Indeed, Dr. Heydorn admitted that, if these patients were unblinded, the fact that the study
was negative without them “undermine[s] the assertions that Study 18’s outcome was positive
for showing Celexa significantly improved major depression disorder in children and
adolescents[.]”132 When Dr. Heydorn was shown the internal documents demonstrating that the
integrity of the blind was unmistakenly violated, he conceded Forest was not honest with the
FDA, that Forest misled people about the results of MD-18, and that he would have written the
study report differently:

Q. Do you have any regrets about your involvement with the CIT-MD-18
based on what I’ve shown you today?
A. I wish we had done things a little differently.

Q. Like what?
A. I wish I had known for certain whether the patients, those nine patients
were unblinded, but obviously I don’t know. You showed me a lot of
documents today suggesting that people knew the patients were unblinded.
I don’t know for a fact that they knew that. All I know is what they wrote
on the paper. I wish I was aware of the correspondence with the FDA.

Q. Do you think, based on what I’ve shown you today, that Forest misled
anyone about the results of MD-18?
A. It probably should have been more forthcoming.
. . .
Q. Would you have changed anything in the final study report?
A. If I were the only one involved in writing it, I probably would have
written it somewhat differently.133

When Dr. Heydorn’s testimony was presented to Dr. Laughren, he testified:

Q. It appears based on Dr. Heydorn’s testimony, he did not believe that the
final study report was fully up front or forthcoming with the FDA; isn’t
that true?
[A]. That’s what he’s saying.

Q. And he’s the man who actually was responsible for the final study report
for Study MD-18, right?
[A]. He appears to have been, yes.

Q. Does it concern you that Dr. Heydorn, who was a former FDA employee
himself, thinks that Forest was not as forthcoming as it should have
been with the FDA about its representation of the results from MD-18?
[A]. Yes.134

The original draft of the MD-18 study report was prepared by a company called PharmaNet,
a contract research organization.135 Before the first draft of the report was prepared, Dr. Flicker,
Dr. Heydorn, and two biostatisticians from Forest met with PharmaNet to discuss how the report
should be prepared.136 The notes of the meeting illustrate Forest’s general strategy in dealing
with the unblinded patients:

Dosing error – some citalopram table[t]s were not blinded. The 9 patients who

received unblinded medication were included in the main analyses; a secondary

“Post-hoc analysis of the ITT subpopulation” was done. Refer to these analyses

briefly in methods and results and reference the reader to the appendix table.137

Thus, from the outset, Forest intended to bury the impact of the unblinded data by referring
“to these analyses briefly” and referencing “the reader to the appendix table” on page 244 (of
2,135). It is also worth noting that, even here, in this meeting, Forest was once again stating that
the drugs “were not blinded” and that the 9 patients “received unblinded medication.” As shown
below, this clear admission of unblinding was deliberately removed from the final study report
sent to the FDA.

In the final study report for MD-18, there are four references to the unblinded patients and all
of them are misleading or factually false. The first reference is in a section of the Study Report
titled “Blinding” where it states:

Because of a drug packaging error, the citalopram or placebo tablets initially

dispensed to 9 patients at 3 study centers were distinguishable in color, although

otherwise blinded (see Section 7.0). When this error was identified at the

beginning of the study period, all study medication shipments were replaced in

full with tablets of identical color to remove any potential for unblinding.138

This paragraph is riddled with inaccuracies and misstatements. First, the placebo tablets
initially dispensed were not distinguishable in color—only the Celexa group received the pink
pills, which is why the investigators were unblinded. If both the placebo and Celexa pills had
been pink, then the investigators would not necessarily have known which patients were assigned
to each group. Second, they were not just distinguishable in color—the pink pills were Foreststamped,
dose-stamped, commercial Celexa tablets. The failure of Forest to disclose that the
drug dispensed was commercial branded Celexa is misleading in the extreme. Third, when this
error was identified, the medication for those patients not yet randomized was replaced, but for
the nine patients already in the study, Forest did not replace their medications.139 Forest
instructed each site to continue using the multicolor pills for those patients already randomized to
placebo.140 That means those Celexa patients received white pills for the screening period, pink
pills for the first four weeks, and then white pills for the last four weeks. This paragraph falsely
stated that these patients’ medication was replaced “to remove any potential for unblinding” and
this is simply not true.

Notably, in the original draft of the MD-18 study report prepared by PharmaNet, a section of
the study report contained the language from the original protocol, specifying that “[a]ny patient
for whom the blind had been broken was to be immediately discontinued from the study and no
further efficacy evaluations were to be performed.”141 Dr. Flicker, however, crossed this
language out and inserted the language that ultimately made its way into the final study report: