Exocrine Pancreatic Insufficiency Drug Products for Over-The- Counter Human Use

[[Page 20162]]

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 310

[Docket No. 79N-0379]

RIN 0905-AA06

Exocrine Pancreatic Insufficiency Drug Products for Over-The-

Counter Human Use

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule

establishing that over-the-counter (OTC) exocrine pancreatic

insufficiency drug products (drug products used to treat pancreatic

enzyme deficiency) are not generally recognized as safe and effective

and are misbranded. FDA is issuing this final rule after considering

public comments on the agency's notice of proposed rulemaking and all

new information on OTC exocrine pancreatic insufficiency drug products

that has come to the agency's attention. This final rule is part of the

ongoing review of OTC drug products conducted by FDA.

EFFECTIVE DATE: October 24, 1995.

FOR FURTHER INFORMATION CONTACT: William E. Gilbertson, Center for Drug

Evaluation and Research (HFD-810), Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857, 301-594-5000.

SUPPLEMENTARY INFORMATION:

I. Background

In the Federal Register of December 21, 1979 (44 FR 75666), FDA

published, under Sec. 330.10(a)(6) (21 CFR 330.10(a)(6)), an advance

notice of proposed rulemaking to establish a monograph for OTC exocrine

pancreatic insufficiency drug products, together with the

recommendations of the Advisory Review Panel on OTC Miscellaneous

Internal Drug Products (the Panel), which was the advisory review panel

responsible for evaluating data on the active ingredients in this drug

class. Interested persons were invited to submit comments by April 21,

1980. Reply comments in response to comments filed in the initial

comment period could be submitted by May 21, 1980.

In accordance with Sec. 330.10(a)(10), the data and information

considered by the Panel were placed on public display in the Dockets

Management Branch (HFA-305), Food and Drug Administration, rm. 1-23,

12420 Parklawn Dr., Rockville, MD 20857, after deletion of a small

amount of trade secret information. Only five comments were submitted

in response to the publication of the advance notice of proposed

rulemaking.

The agency's proposed regulation, in the form of a tentative final

monograph, for OTC exocrine pancreatic insufficiency drug products was

published in the Federal Register of November 8, 1985 (50 FR 46594).

That proposal constituted FDA's tentative adoption of the Panel's

conclusions and recommendations on OTC exocrine pancreatic

insufficiency drug products as modified on the basis of the comments

received and the agency's independent evaluation of the Panel's report

and information available at that time. In that document, the agency

accepted the Panel's recommendation that exocrine pancreatic

insufficiency drug products be available as OTC drug products and

proposed the conditions under which these drug products would be

generally recognized as safe and effective and not misbranded.

Interested persons were invited to file by January 7, 1986, written

comments, objections, or requests for oral hearing before the

Commissioner of Food and Drugs (the Commissioner) regarding the

proposal, and by March 10, 1986, to file comments on the agency's

economic impact determination. New data could have been submitted until

November 10, 1986, and comments on the new data until January 8, 1987.

New information submitted in response to the tentative final

monograph caused the agency to reconsider the approach proposed in that

document. In vivo and in vitro studies of various commercial pancreatic

enzyme preparations had demonstrated variations in lipase activity and

release rates among the products. These variations in pancreatic

extract drug products occurred both among various dosage forms and

among products from different manufacturers of the same dosage form. In

addition, problems had been reported with pancreatic extract products

manufactured as tablets with enteric coatings and as encapsulated

enteric-coated microspheres. As a result of the wide range of enzyme

activity in these products, the variety of dosage forms marketed, and

the apparent uneven quality of the enteric coatings among pancreatic

extract drug products, instances of underdosing and overdosing with

pancreatic extract products have occurred. The agency determined that

preclearance of each product in order to standardize enzyme bioactivity

was necessary to avoid serious safety problems resulting from too

little or too much enzyme supplementation. The agency tentatively

concluded that an OTC drug monograph would not be sufficient to

adequately regulate these drug products. The agency discussed these

problems in the Federal Register of July 15, 1991 (56 FR 32282 at 32286

and 32287).

In that notice, FDA proposed to classify OTC drug products to treat

exocrine pancreatic insufficiency as not generally recognized as safe

and effective, as being misbranded, and as new drugs within the meaning

of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act)

(21 U.S.C. 321(p)). FDA proposed to amend part 310, subpart E by adding

new Sec. 310.543 (21 CFR 310.543) for OTC exocrine pancreatic

insufficiency drug products. The agency also withdrew its proposed rule

(part 357, subpart E) issued on November 8, 1985. Interested persons

were invited to file by November 12, 1991, written comments,

objections, or requests for oral hearing on the proposed regulation

before the Commissioner, and to file comments on the agency's economic

impact determination by November 12, 1991. Final agency action occurs

with the publication of this final rule on OTC exocrine pancreatic

insufficiency drug products.

In the Federal Register of March 11, 1992 (57 FR 8586), the agency

reopened the administrative record and announced that a workshop would

be held on April 23, 1992, to discuss testing procedures that will be

required as part of new drug applications (NDA's) for all exocrine

pancreatic insufficiency drug products. Relevant data and notice of

participation were to be submitted by April 10, 1992. The

administrative record remained open until July 23, 1992, to receive

comments regarding matters raised at the workshop.

In response to the announcement of the workshop, eight notices of

participation and three comments were submitted. Copies of the

comments, notices received, and information coming to the agency's

attention after the workshop are also on public display in the Dockets

Management Branch (address above). At the conclusion of the workshop,

manufacturers were encouraged to arrange pre-NDA meetings with agency

personnel so that NDA submissions could proceed as quickly as possible

(Ref. 1).

This final rule amends part 310 to include drug products containing

ingredients for the treatment of exocrine pancreatic insufficiency by

adding new [[Page 20163]] Sec. 310.543 to subpart E. The inclusion of

OTC exocrine pancreatic insufficiency drug products in part 310 follows

FDA's established policy for regulations in which there are no

monograph conditions. (See, e.g., Secs. 310.510, 310.519, 310.525,

310.526, 310.532, 310.533, 310.534, and 310.546.) It is the agency's

intent that exocrine pancreatic insufficiency drug products be marketed

by prescription only. However, if, in the future, any ingredient is

determined to be generally recognized as safe and effective for use in

an OTC exocrine pancreatic insufficiency drug product, the agency will

promulgate an appropriate regulation at that time.

FDA no longer uses the terms ``Category I'' (generally recognized

as safe and effective and not misbranded), ``Category II'' (not

generally recognized as safe and effective or misbranded), and

``Category III'' (available data are insufficient to classify as safe

and effective, and further testing is required) at the final rule

stage. In place of Category I, the term ``monograph conditions'' is

used; in place of Category II or III, the term ``nonmonograph

conditions'' is used.

In the proposed rule for OTC exocrine pancreatic insufficiency drug

products (56 FR 32282 at 32283), the agency advised that the final rule

for these drug products would be effective 6 months after the date of

its publication in the Federal Register. Therefore, on or after October

24, 1995, no OTC drug products that are subject to this final rule may

be initially introduced or initially delivered for introduction into

interstate commerce unless they are the subject of an approved

application. The agency is unaware of any OTC exocrine pancreatic

insufficiency drug products that are the subject of an approved

application. Any such drug product in interstate commerce after the

effective date of this final rule that is not in compliance with the

regulation is subject to regulatory action.

In response to the proposed rule on OTC exocrine pancreatic

insufficiency drug products, five drug manufacturers, one foundation,

and three individuals submitted comments. Copies of the comments

received and any additional information that has come to the agency's

attention since publication of the proposed rule are on public display

in the Dockets Management Branch (address above).

Reference

(1) Comment No. MM1, Docket No. 79N-0379, Dockets Management

Branch.

II. The Agency's Conclusions on the Comments

1. Six comments (including the Cystic Fibrosis Foundation and the

American Academy of Pediatrics) agreed with the agency's proposal that

exocrine pancreatic insufficiency drug products should not be marketed

OTC. Three comments opposed the proposal. Two of those comments stated

that increased costs to consumers would include a physician's fee and a

higher markup when sold by prescription. The third comment indicated

that these products are currently reasonably priced as nonprescription

drugs.

The agency appreciates the support of the six agreeing comments and

is finalizing its proposal that all exocrine pancreatic insufficiency

drug products should be available only by a doctor's prescription. The

agency stated in the proposed rule that continuous physician monitoring

of patients appears to be one of several important factors in the

increased survival rates for exocrine pancreatic insufficiency patients

(56 FR 32282 at 32285). Accordingly, such collateral measures necessary

to the use of these drug products require that they be available by

prescription only, as required by section 503(b)(1)(B) of the act (21

U.S.C. 353(b)(1)(B)). The agency acknowledges the cost concerns raised

by the three opposing comments. However, as stated in the proposed rule

(56 FR 32282 at 32285), financial considerations are not among the

statutory criteria for determining whether a drug product should be

restricted to prescription status.

2. Two comments disagreed with the agency's proposal that NDA

approval be required for continued marketing of all exocrine pancreatic

insufficiency drug products. One comment stated that the proposal is

inconsistent with the Panel's and the agency's previous conclusion that

these products have been safely used to treat exocrine pancreatic

insufficiency for many years (50 FR 46594 at 46597). The comment

contended that the July 15, 1991, proposal did not contain any new

evidence showing that the initial conclusion was erroneous. The comment

stated that the agency's concerns are based on a perceived inability of

patients to treat themselves and mentioned that this problem could be

remedied by requiring these products to be available by prescription,

without the need for an NDA for continued safe and effective use. The

comment contended that an NDA requirement would have a devastating

effect on patients who require these products for survival, e.g.,

cystic fibrosis patients. The comment surmised that most manufacturers

would withdraw their exocrine pancreatic insufficiency drug products

from the market if an NDA were required, primarily because of NDA-

associated costs. The comment added that manufacturers would wait until

another manufacturer's application was approved so they could submit an

abbreviated NDA. A third comment made a number of suggestions for the

bioactivity testing requirements, urged that certain products that had

been extensively used and studied be granted approval on the basis of

published reports and in vitro data, and contended that placebo-

controlled safety and effectiveness studies in cystic fibrosis patients

are unethical.

The agency disagrees with the first two comments. The agency's

position on exocrine pancreatic insufficiency drug products changed

between 1985 and 1991. Based on variations in formulations and dosage

forms, e.g., encapsulated microsphere dosage forms, in use in 1991, the

agency determined that final formulation effectiveness testing and

information on the product's formulation, manufacture, and quality

control procedures are necessary to ensure that a company has the

ability to manufacture a proper, bioactive formulation (56 FR 32282 at

32283). Because there are no approved NDA's for any exocrine pancreatic

insufficiency drug products, the agency has no information on the

bioactivity of these products. The agency notes that even if all

products were available only by prescription, variances in bioactivity

of final formulations could pose safety concerns. Additional

information (which an NDA would contain) is needed to assure safe and

effective use of these products. Bioactivity must be shown to correlate

with the stated potency of each proposed product, particularly for

newer formulations that include microspheres and high potency levels of

the pancreatic enzymes.

The agency is not persuaded by the comment's suggestion that

manufacturers would not submit applications for pancreatic enzyme

products and would wait until abbreviated NDA's were possible. The

agency acknowledges that a number of manufacturers are currently

seeking NDA approval for their currently marketed exocrine pancreatic

insufficiency drug products.

The agency has received a number of reports of occurrences of

stricture of the colon in cystic fibrosis patients who had taken higher

potency pancreatic enzymes in delayed release microtablets and

microspheres for varying numbers of months prior to corrective surgery

[[Page 20164]] (Refs. 1 through 8). The agency is concerned that there

may be a relationship between the use of these formulations and

stricture of the colon. The agency needs to evaluate manufacturing

information for these formulations, which would be included in an NDA.

The third comment's suggested bioactivity testing requirements,

support for approval of certain products, and opposition to placebo-

controlled studies are outside the scope of this document. The agency

notes, however, that it is widely believed that demonstration of the

fat digestive actions of various preparations can be done in ethical

human studies. Inquiries relating to these subjects should be directed

to the Division of Gastrointestinal and Coagulation Drug Products (HFD-

180), Center for Drug Evaluation and Research, Food and Drug

Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-443-0479.

References

(1) Cystic Fibrosis Foundation Results of a Survey of 114 Cystic

Fibrosis Care Centers in United States, Patient Registry 1992 Annual

Data Report, Bethesda, MD, October 1993, in OTC Vol. 17BFR, Docket

No. 79N-0379, Dockets Management Branch.

(2) Smyth, R. L. et al., ``Strictures of Ascending Colon in

Cystic Fibrosis and High-Strength Pancreatic Enzymes,'' Lancet,

343:85-86, 1994.

(3) Oades, P. J. et al., ``Letter to the Editor,'' Lancet,

343:109, 1994.

(4) Campbell, C. A., J. Forrest, and C. Musgrove, ``Letter to

the Editor,'' Lancet, 343:109, 1994.

(5) Briars, G. L. et al., ``Letter to the Editor,'' Lancet,

343:600, 1994.

(6) Mahony, M. J., and M. Corcoran, ``Letter to the Editor,''

Lancet, 343:599-600, 1994.

(7) Knabe, N. et al., ``Letter to the Editor,'' Lancet,

343:1230, 1994.

(8) Taylor, C. J., ``Colonic Strictures in Cystic Fibrosis,''

Lancet, 343:615-616, 1994.

3. As an alternative to the NDA process, one comment recommended

that a uniform convention be developed for labeling exocrine pancreatic

insufficiency drug products to clearly describe product potency. The

comment urged that labels include the expiration date and rate of loss

of potency, and indicate that proprietary agents are not generally

equivalent.

The agency disagrees with the comment's alternative to the NDA

process. Uniform labeling to describe product potency is important;

however, that alone will not ensure safety and effectiveness of these

products. The comment's labeling suggestions will be considered, based

on data considered in applications, as NDA's for these products are

approved. These issues are outside of the scope of this rulemaking.

4. One comment urged the agency not to issue a final rule for OTC

exocrine pancreatic insufficiency drug products until NDA's for these

products have been approved. Alternatively, the comment asked that the

agency withdraw its proposal and request that NDA's be submitted for

exocrine pancreatic insufficiency drug products. The comment contended

that the latter action would be similar to the agency's action in 1978

regarding potassium iodide. The comment stated that either approach

would guarantee the availability of these products to patients who are

benefitting from them.

The agency disagrees with both of the comment's suggestions. In the

Federal Register of December 15, 1978 (43 FR 58798), the agency

published a notice requesting submission of NDA's for potassium iodide

in oral dosage forms for use as a thyroid-blocking agent in a radiation

emergency. The Commissioner concluded that potassium iodide was safe

and effective under certain specified conditions of use. However, the

Commissioner did not conclude that potassium iodide was generally

recognized as safe and effective (43 FR 58798 at 58799). Therefore,

potassium iodide was regarded as a new drug requiring an approved NDA

as a condition of marketing.

Exocrine pancreatic insufficiency drug products are a similar

situation. These products are safe and effective under specified

conditions of use, but their bioactivity raises both safety and

effectiveness concerns that require agency preclearance under NDA's.

The agency sees no reason to withdraw its proposal because the final

rule resulting from that proposal requires that an NDA be submitted for

any exocrine pancreatic insufficiency drug product marketed OTC.

Manufacturers have known since 1991 that an approved NDA would be

needed for continued marketing of their product(s) on an OTC basis.

While this final rule affects availability of these products when

marketed OTC, it does not affect products marketed on a prescription

basis. The agency intends that exocrine pancreatic insufficiency drug

products marketed by prescription also have an approved NDA. All

manufacturers of prescription exocrine pancreatic insufficiency drug

products will need to have an NDA for their product(s). The agency will

address this subject further in a future issue of the Federal Register.

III. The Agency's Final Conclusions on OTC Exocrine Pancreatic

Insufficiency Drug Products

A number of pancreatic enzyme drug products are currently marketed

OTC, and other products are marketed by prescription. Some of the

prescription products are encapsulated enteric coated microsphere

dosage forms. None of these pancreatic enzyme drug products have

approved applications, i.e, none have been precleared for marketing by

FDA. Some products are produced by different manufacturers and contain

the same active ingredient(s); however, these products have shown

significant differences in bioavailability. The agency finds that these

differences raise a potential for serious risk to patients using these

products.

Based on all available evidence, the agency has determined that the

bioavailability of pancreatic enzymes is dependent on the process used

to manufacture the drug products. Information on this process is not

addressed by an OTC drug monograph. Therefore, the agency has

determined that the safe and effective use of these enzymes for

treating exocrine pancreatic insufficiency cannot be regulated

adequately by an OTC drug monograph. In this final rule, the agency is

declaring that all exocrine pancreatic insufficiency drug products

(whether currently marketed on an OTC or prescription basis) are new

drugs for which approved applications will be required for marketing.

In the Federal Register of November 7, 1990 (55 FR 46914), the

agency published a final rule in part 310 establishing that certain

active ingredients that had been under consideration in a number of OTC

drug rulemaking proceedings were not generally recognized as safe and

effective. That final rule was effective on May 7, 1991, and included

in Sec. 310.545(a)(9) the ingredient hemicellulase, which had been

previously considered under this rulemaking for OTC exocrine pancreatic

insufficiency drug products. In order to avoid duplication in listing

OTC exocrine pancreatic insufficiency active ingredients in more than

one regulation, and for ease in locating these ingredients in the Code

of Federal Regulations, the agency is listing all of these ingredients

in a single regulation in new Sec. 310.543 entitled ``Drug products

containing active ingredients offered over-the-counter (OTC) for human

use in exocrine pancreatic insufficiency.'' Accordingly, the ingredient

hemicellulase, currently listed in Sec. 310.545(a)(9) is now being

listed in Sec. 310.543(d), and Sec. 310.545(a)(9) is being removed and

reserved. The ingredients pancreatin and pancrelipase, covered by this

final rule, are being listed in Sec. 310.543(e). [[Page 20165]]

IV. Analysis of Impacts

An analysis of the costs and benefits of this regulation, conducted

under Executive Order 12291 was discussed in the proposed rule (56 FR

32282 at 32289). Comments received were discussed in part II of this

final rule. Executive Order 12291 has been superseded by Executive

Order 12866.

FDA has examined the impacts of the final rule under Executive

Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354).

Executive Order 12866 directs agencies to assess all costs and benefits

of available regulatory alternatives and, when regulation is necessary,

to select regulatory approaches that maximize net benefits (including

potential economic, environmental, public health and safety, and other

advantages; distributive impacts; and equity). The agency believes that

this final rule is consistent with the regulatory philosophy and

principles identified in the Executive Order. In addition, the final

rule is not a significant regulatory action as defined by the Executive

Order and, so, is not subject to review under the Executive Order.

The Regulatory Flexibility Act requires agencies to analyze

regulatory options that would minimize any significant impact of a rule

on small entities. This final rule will result in the removal of all

drug products containing the ingredients pancreatin and pancrelipase

from the OTC marketplace. However, only a limited number of OTC drug

products are marketed in this manner and are affected by this final

rule. Accordingly, the agency certifies that the final rule will not

have a significant economic impact on a substantial number of small

entities. Therefore, under the Regulatory Flexibility Act, no further

analysis is required.

The agency has determined under 21 CFR 25.24(c)(6) that this action

is of a type that does not individually or cumulatively have a

significant effect on the human environment. Therefore, neither an

environmental assessment nor an environmental impact statement is

required.

List of Subjects in 21 CFR Part 310

Administrative practice and procedure, Drugs, Labeling, Medical

devices, Reporting and recordkeeping requirements.

Therefore, under the Federal Food, Drug, and Cosmetic Act and under

authority delegated to the Commissioner of Food and Drugs, 21 CFR part

310 is amended as follows:

PART 310--NEW DRUGS

1. The authority citation for 21 CFR part 310 continues to read as

follows:

Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 512-

516, 520, 601(a), 701, 704, 705, 721 of the Federal Food, Drug, and

Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357,

360b-360f, 360j, 361(a), 371, 374, 375, 379(e); secs. 215, 301,

302(a), 351, 354-360F of the Public Health Service Act (42 U.S.C.

216, 241, 242(a), 262, 263b-263n).

2. New Sec. 310.543 is added to subpart E to read as follows:

Sec. 310.543 Drug products containing active ingredients offered over-

the-counter (OTC) for human use in exocrine pancreatic insufficiency.

(a) Hemicellulase, pancreatin, and pancrelipase have been present

as ingredients in exocrine pancreatic insufficiency drug products.

Pancreatin and pancrelipase are composed of enzymes: amylase, trypsin

(protease), and lipase. Significant differences have been shown in the

bioavailability of marketed exocrine pancreatic insufficiency drug

products produced by different manufacturers. These differences raise a

potential for serious risk to patients using these drug products. The

bioavailability of pancreatic enzymes is dependent on the process used

to manufacture the drug products. Information on this process is not

included in an OTC drug monograph. Therefore, the safe and effective

use of these enzymes for treating exocrine pancreatic insufficiency

cannot be regulated adequately by an OTC drug monograph. Information on

the product's formulation, manufacture, quality control procedures, and

final formulation effectiveness testing are necessary in an approved

application to ensure that a company has the ability to manufacture a

proper bioactive formulation. In addition, continuous physician

monitoring of patients who take these drug products is a collateral

measure necessary to the safe and effective use of these enzymes,

causing such products to be available by prescription only.

(b) Any drug product that is labeled, represented, or promoted for

OTC use in the treatment of exocrine pancreatic insufficiency is

regarded as a new drug within the meaning of section 201(p) of the

Federal Food, Drug, and Cosmetic Act (the act), for which an approved

application under section 505 of the act and part 314 of this chapter

is required for marketing. In the absence of an approved application,

such product is also misbranded under section 502 of the act.

(c) Clinical investigations designed to obtain evidence that any

drug product labeled, represented, or promoted for OTC use in the

treatment of exocrine pancreatic insufficiency is safe and effective

for the purpose intended must comply with the requirements and

procedures governing the use of investigational new drugs set forth in

part 312 of this chapter.

(d) After May 7, 1991, any such OTC drug product that contains

hemicellulase initially introduced or initially delivered for

introduction into interstate commerce that is not in compliance with

this section is subject to regulatory action.

(e) After October 24, 1995, any such OTC drug product that contains

pancreatin or pancrelipase initially introduced or initially delivered

for introduction into interstate commerce that is not in compliance

with this section is subject to regulatory action.

Sec. 310.545 [Amended]

3. Section 310.545 Drug products containing certain active

ingredients offered over-the-counter (OTC) for certain uses is amended

by removing and reserving paragraph (a)(9), and by revising paragraph

(d)(1) to read as follows:

Sec. 310.545 Drug products containing certain active ingredients

offered over-the-counter (OTC) for certain uses.

(d) * * *

(1) May 7, 1991, for products subject to paragraphs (a)(1) through

(a)(4), (a)(6)(i)(A), (a)(6)(ii)(A), (a)(7) (except as covered by

paragraph (d)(3) of this section), (a)(8)(i), (a)(10)(i) through

(a)(10)(iii), (a)(12)(i) through (a)(12)(iv), and (a)(14) through

(a)(18)(i) of this section.

* * * * *

Dated: April 13, 1995.

William K. Hubbard,

Acting Deputy Commissioner for Policy.

[FR Doc. 95-10078 Filed 4-21-95; 8:45 am]

BILLING CODE 4160-01-F