PHARMACEUTICAL MANUFACTURING RESEARCH SERVICES, INC.

September 04, 2020

Via Electronic Submission

Division of Dockets Management

Food and Drug Administration
Department of Health and Human Services
5630 Fishers Lane, Room 1061
Rockville, MD 20852

RE: Docket No. FDA-2020-N-0982

In regard to FDA’s analysis of the required postmarketing studies that evaluated the effect of the
reformulation of OxyContin on abuse, misuse, and overdose, FDA is under a significant burden
to affirmatively demonstrate that their reliance on premarket data inexorably leads to
postmarketing evidence.1 Past FDA decisions, such as the approval and abuse-deterrent labeling
of reformulated OxyContin, combined with the removal of original OxyContin for reasons of
safety, clearly establish that FDA makes postmarketing decisions on the basis of premarket
hypotheses, and absent postmarketing evidence. Yet there is no conclusive justification that such
premarket assessments will ever lead to a meaningful reduction in abuse. Furthermore, there are
numerous issues in regards to FDA’s approval and labeling of reformulated OxyContin, which
fatally invalidate the actual purpose of the required postmarketing studies. Simply put,
reformulated OxyContin does not have physicochemical properties that deter abuse.

I. Reformulated OxyContin’s physicochemical properties fail to deter manipulation

Summary: If you can cut it; if you have access to water; and if you have a syringe, then you can
IV 16mg/mL of oxycodone from one reformulated OxyContin tablet. Reformulated OxyContin,
as a drug product, does not deter abuse.

1
FDA has stated, “As is evident from the guidance document, the Agency considers Category 3 human abuse-
deterrent (liking) studies to have relevance in assessing abuse-deterrent effects and predicting possible routes of
abuse of a product once on the market” (emphasis added), but does not provide justification for this belief. See
FDA Reference ID: 3969519, p. 9. Indeed, FDA acknowledges this tenuous relationship in its Guidance: “FDA has
limited data correlating the abuse-deterrent properties of certain opioid drug products, as demonstrated by premarket
studies, with the impact of those properties on abuse or adverse events associated with abuse in the post-approval
setting.”

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In 2016 we notified the FDA that a simple method existed in which a reformulated OxyContin
tablet can be manipulated into a highly potent injectable solution in 30 minutes.2 Extraction and
injection of reformulated OxyContin in this manner can be accomplished by an untrained,
unskilled person on their first attempt using only scissors3 and water. A demonstration of this
technique has been provided to FDA in the form of a 9-minute film.4 This film should have been
shown to the advisory committee as a full-disclosure requirement.

Figure 1 – Reformulated OxyContin 80mg can easily be cut in half with scissors

2
Citizen Petition from Pharmaceutical Manufacturing Research Services, Docket ID FDA-2016-P-0645, February
26, 2016, p. 11, accessed September 04, 2020 from https://www.regulations.gov/docket?D=FDA-2016-P-0645
3
FDA has offered contradictory assessments in regards to reformulated OxyContin resistance to physical
manipulation. See FDA-2018-P-4338-0001, pp. 21-22. Our testing indicates that the FDA Controlled Substance
Staff review is the most accurate: “Reformulated OxyContin has no meaningful advantage in breaking and crushing
over original OxyContin”. See U.S. Food and Drug Administration, Center for Drug Evaluation and Research,
OxyContin NDA 22-272, S-014 Division Director Review, February 6, 2013, p. 8, accessed September 04, 2020
from https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/022272Orig1s014SumR.pdf.
4
OxyContin Modification, accessed September 04, 2020 from https://www.regulations.gov/document?D=FDA-
2018-N-0188-0273.

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Figure 2 – Small-volume extraction of Reformulated OxyContin in water

The demonstrated extraction methodology is not novel or complex, and had apparently been
known to the FDA prior to approving abuse-deterrent labeling. During their review, the FDA
Controlled Substance Staff reported, “Water is also effective in extracting oxycodone HCl from
intact tablets of reformulated OxyContin. Thus, a simple water extraction procedure can afford
clinically significant amounts of oxycodone from high strengths of intact and crushed tablets of
both the original and reformulated product.”5

Yet in approving abuse-deterrent labeling for OxyContin, then-Division Director Dr. Bob
Rappaport made the contradictory conclusion, “These features also render the product almost
impossible to dissolve, syringe and inject.”6

5
FDA Reference ID: 3292186, p. 4.
6
FDA Reference ID: 3293880, p. 2.

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Figure 3 – Reformulated OxyContin can be readily extracted into a syringable solution

Doubling down, Dr. Douglas Throckmorton, Deputy Director, CDER, reported to Dr. Janet
Woodcock his recommendation for approving abuse-deterrent labeling, citing, “OCR gradually
forms a viscous hydrogel (i.e. a gelatinous mass) that resists passage through a needle. The in
vitro testing was sufficient to demonstrate that OCR prevents oxycodone from being drawn into
a syringe to any meaningful extent.”7

7
FDA Reference ID: 329414, p. 9.

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Figure 4 – Reformulated OxyContin extraction produces a clear, non-viscous liquid for injection at 9-16mg/mL

As evaluated against the context of the plain evidence demonstrating the ease in which
reformulated OxyContin can be manipulated, both of FDA’s cherry-picked conclusions illustrate
the gaping disconnect between the actual physicochemical properties of the reformulated drug
product and the false and misleading claims of abuse deterrence communicated in the label.8,9

These properties preclude reformulated OxyContin from having meaningful abuse-deterrent

properties.

8
Food and Drug Administration, Highlights of Prescribing Information OxyContin®, December 2016, pp. 18-22,
accessed on September 04, 2020 from
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/022272Orig1s014Lbl.pdf.
9
Food and Drug Administration, Highlights of Prescribing Information OxyContin®, October 2019, pp. 28-33,
accessed on September 04, 2020 from
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022272s043lbl.pdf.

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II. Reformulated OxyContin has no impact on intranasal abuse

Summary: Intranasal abuse of oxycodone in any formulation is a less enticing/less dangerous

route of abuse than oral. An abuser will get more drug faster from oral abuse, rather than
intranasal abuse. Study results approved by the FDA confirm these results, demonstrating that
manipulated oxycodone taken orally produces higher and faster blood levels of narcotic than
manipulated oxycodone taken nasally.

FDA’s decision to approve reformulated OxyContin with abuse-deterrent labeling for the
intranasal route is also problematic and contradictory. The FDA-approved labeling for
reformulated OxyContin states, “The data from the clinical study, along with support from the in
vitro data, also indicate that OXYCONTIN has physicochemical properties that are expected to
reduce abuse via the intranasal route.”10

For oxycodone products, declaration of abuse deterrence for the nasal route is a mere
smokescreen that does nothing to protect the American public. Despite FDA advocacy for the
development and classification of products with claimed abuse-deterrent properties for this route,
there is no scientific evidence that intranasal abuse of oxycodone is a more effective route of
abuse for oxycodone than oral abuse. Furthermore, existing pharmacokinetic data actually
refutes the nasal route of abuse as a means of providing a stronger or faster drug "high".

Multiple drug product sponsors have presented measurable, reproducible data to the FDA on
oxycodone blood levels for the oral and nasal routes of administration for 30 and 40 mg dosage
strengths. This data includes both intact and manipulated dosage forms and has been aggregated
in Figure 5 for Cmax blood levels. In the context of abuse, a product with a higher Cmax
(greater maximum blood concentration) is more prone to abuse. When evaluating Cmax
between the nasal and oral routes of abuse, it is readily apparent the oral route offers an equal or
greater Cmax when compared to nasal abuse.11

10
See n. 11 at p. 22.
11
Citizen Petition from Pharmaceutical Manufacturing Research Services, Docket ID FDA-2018-P-4338, November
15, 2018, p. 31, accessed September 04, 2020 from https://www.regulations.gov/docket?D=FDA-2018-P-4338

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This chart (Figure 5) demonstrates that manipulated oxycodone taken orally is superior to
manipulated oxycodone taken nasally.

Figure 5 - Oxycodone by the oral route produces a higher Cmax than the intranasal route

In brief: Oral beats intranasal, beats IR oxycodone, and beats Roxicodone. It’s the drug—not the
formulation.

For oxycodone, oral is clearly the superior route of abuse when compared to nasal. Oral offers a
greater high than intranasal administration, and this also comes at a faster rate. Additionally, this
supports the conclusion that the oral route is a more dangerous route than the nasal route. Due to
the greater and faster high, oral presents a greater potential for lethal overdose of oxycodone than
intranasal administration.

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This is additionally supported by DEA medical examiner reports (data as of 200212; referenced
by FDA in 201313) which indicate that 96% of OxyContin deaths are due to oral abuse,
compared to 2% for intravenous and 0.2% for intranasal. Lastly, the nasal route is irrelevant to
abuse deterrence in the context of oxycodone. Given the oral route's superior pharmacokinetics,
there is no incentive beyond preconceived and erroneous notions about the drug to abuse
oxycodone intranasally.

The plain facts regarding the superior oral route of abuse for oxycodone—which is already
known on the street, dating back at least to 201114,15—demonstrates the pointlessness of
attempting to label an oxycodone ADF formulation for either intranasal or intravenous abuse
without addressing oral abuse.

Creating—and approving—an abuse-deterrent formulation for the purpose of reducing intranasal

abuse is nonsensical.

III. Epidemiologic data cannot reverse the enormous increase in consumption of

reformulated OxyContin

Summary: Production data indicates that the introduction of reformulated OxyContin did not
reduce either the overall production or consumption of oxycodone.

The entrance of original OxyContin on the market in 1996 led to an enormous increase in the
annual consumption volume of oxycodone HCl in the US. This increase can be clearly seen in
the federally-approved oxycodone production quota, which had grown by nearly 17 times in
2009, when compared to the quota at the start of OxyContin’s marketing in 1996. The approval
of reformulated OxyContin in 2010 included purported abuse-deterrent properties which would
deter, and therefore reduce, OxyContin’s abuse and misuse. Were this formulation effective in
curbing abuse, the portion of consumption generated by abusers would be expected to decrease.
In turn, this would lead to a decrease in oxycodone HCl consumption, and a similar decrease in
production quota.

12
U.S Department of Justice, Drug Enforcement Administration, Office of Diversion Control. Summary of Medical
Examiner Reports on Oxycodone-Related Deaths, accessed September 04, 2020 from
https://web.archive.org/web/20130304035640/http://www.deadiversion.usdoj.gov/drugs_concern/oxycodone/oxyco
ntin7.htm.
13
FDA Reference ID 3258740, p. 5.
14
Oxycodone insufflation bioavailability vs. oral bioavailability. Bluelight, August 28, 2011, accessed September
04, 2020 from http://www.bluelight.org/xf/threads/oxycodone-insufflation-bioavailability-vs-oral-
bioavailability.587232/
15
Hip Forums, accessed July 23, 2018, https://www.hipforums.com/forum/threads/to-the-people-who-only-snort-
oxycodone.336603/

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However, OxyContin’s reformulation had the opposite effect. Consumption of oxycodone HCl
continued to grow unfettered, resulting in record production quotas over the following years.
Consumption increased to such an extent, that the production quota of oxycodone HCl did not
return to pre-reformulation levels until 2018. This turns OxyContin’s claims of abuse-deterrence
on their head. With increases in consumption and quota in the years following the
reformulation’s approval, it is clear the reformulation had no impact on the demand generated by
abusers.

Figure 6 – Federally-approved 1995 to 2021 production quota of OxyContin

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IV. Reformulated OxyContin did not shift misuse, abuse, and deaths to heroin

Summary: As evaluated by leading experts at NIH and CDC, the introduction of the “abuse-
deterrent” reformulation of OxyContin did not lead to an increase in heroin abuse.

In a study authored by leading experts at NIH and CDC, the introduction of reformulated
OxyContin did not lead to an increase in heroin abuse. As published in NEJM by Compton,
Jones, and Baldwin in 2016, “Heroin use has been increasing in the United States for the past 10
years, especially since 2007.”16 They elaborate:

“Multiple studies that have examined why some persons who abuse prescription opioids initiate heroin use
indicate that the cost and availability of heroin were primary factors in this process...It appears that the shift
towards heroin use among some nonmedical users of prescription opioids was occurring before the recent
policy focus on prescription-opioid abuse took hold. This observation is supported by data on heroin use
reported to U.S. poison control centers that show increases starting in 2006, as well as national surveillance data
that show a rise in heroin use starting in 2007.” (emphasis added)17

“The results of studies by Dart et al. and Cicero et al. suggest an association between the introduction of an
abuse-deterrent formulation of OxyContin and increases in rates of heroin use. Dart el al. found evidence that
rates of heroin use increased after the introduction of the abuse-deterrent formulation, but they also reported that
the rate of heroin use was increasing previously. Cicero et al. found that a decrease in the rate of OxyContin
abuse corresponded with an increase in the rate of heroin use over the 2 years after the introduction of the abuse-
deterrent formulation. However, in a follow-up study, Cicero and Ellis found that over the ensuing 18 months,
the rates of OxyContin abuse no longer decreased whereas the rates of heroin use continued to increase.
Moreover, a separate study involving patients who were being screened for substance-abuse treatment showed
no significant differences between the prevalence of heroin use before the introduction of the reformulation and
the prevalence after the reformulated drug was available.” (emphasis added) 18

16
Compton WM, Jones CM, Baldwin J. Relationship between nonmedical prescription-opioid use and heroin use. N
Engl J Med. 2016;374(2):154–63, accessed September 04, 2020 from
https://www.nejm.org/doi/full/10.1056/NEJMra1508490
17
Ibid.
18
Ibid.

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V. Conclusion

Regardless of the FDA's analysis of postmarketing data in regards to reformulated OxyContin,

the readily-abusable formulation of the. drug product itself precludes any theorized impact of the
formulation on levels of abuse, misuse, and overdose. No postmarketing results can be
attributable to the abuse-deterrent properties of the drug formulation, since the drug formulation
does not actually have abuse-deterrent properties. FDA's error in approving abuse-deterrent
labeling on this drug is a critical lapse in judgement, not supported by substantial evidence as
required by law.

Reformulation of OxyContin did not reduce production quota, and it did not reduce abuse. Any
epidemiology findings related to OxyContin cannot be attributable to physicochemical properties
19,20
of the reformulation.

Respectfully Submitted,

Edwin R. Thompson, President

Phannaceutical Manufacturing Research Services, Inc.
202 Precision Road
Horsham, PA 19044

19 Compton et ai., identify marketplace factors as maj or drivers, such as price. See n. 18.
20
FDA has also contributed to making the market. See FDA Reference ID: 3712567, Three-Year Exclusivity
Recommendation/or OxyContin (oxycodone hydrochloride) Controlled-Release Tablets (NDA 022272, S014),
accessed on September 04, 2020, https:llwww.regulations.gov/document?D=FDA-2018-N-0188-0103 .

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