DRUGS AND THE PHARMACEUNCAL SCiEHCES
`
`NEW “Pl!!!
`Alllll‘flVflI PI‘flBBSS
`
`Richard A. Guarino, MD.
`
`Ffllll‘lli Eniiinn
`Accelerating Bimini Regisiiaiiiins
`
`edited by
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`acre-Pharma-
`ko and Ste—
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`Biopharma-
`nn RUttinger
`«Edition. Re-
`tH. Wachter
`ised and Ex-
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`Rolland and
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`hn C. Bloom
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`l Edition, Re-
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`cturing, edited
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`arket, edited by
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`NEW “I‘llfl
`Alllll‘flVfli PI‘IIBBSS
`
`icurth Editicc
`Accelerating iticttel Registrations
`
`edited by
`Richard it. Guarinc, NLD.
`Oxford Pharmaceutical Resources, Inc.
`- mewa. New Jersey, USA.
`
`MARCEL DEKKER, INC.
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`Mylan v. Janssen (IPR2020-00440) Ex. 1037, p. 002
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`

`

`
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`Mylan V. Janssen (IPR2020-00440) EX. 1037 p 003
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`Mylan v. Janssen (IPR2020-00440) Ex. 1037, p. 003
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`10
`Clinical Research Protocols
`
`Richard A. Guarlno
`Oxford Pharmaceutical Resources, Inc., Totowa, New Jersey, U.S.A.
`
`‘3
`
`I.
`INTRODUCTION
`The practice oi“ clinical research—«to establish safety and efficacy for new
`drugs devices. and hielogicalsmis ccnsidered the most important part ofthe
`new drug. approval process by many individuals in the FDA, sponsor
`companies. and users ol‘ pharmaceutical products. Accomplishing this task
`requires careful strategic planning to meet research objectives. an available
`subject population that meets the criteria oi“ trial requirements, and experi-
`enced well trained clinical investigators who can evaluate the trial subjects
`following the protocol design
`Clinical research protocols are key to assuring successful approvals of
`new products in the health care industry. The protocol becomes the Bible
`for each research program. It must be followed exactly, without deviations.
`and must be the reference for any discussions that arise during the course of
`the investigation. This chapter will give instructions on how to write a
`clinical protocol for all phases of clinical research.
`it will
`include all
`necessary FDA requirements for confirming safety and efiicacy for products
`marketed for human use. The format l‘cr protocol development is recom-
`mended on the basis of its successful use in clinical research. The recommen-
`dations throughout this chapter may net always be applicable to all clinical
`programs.The objective of most clinical trials is to record scientific data con-
`cerning the silicate}: and safety of a treatment for at specific disease cm which
`valid conclusions can be drawn. The degree cl" success in achieving this ob-
`jective depends largely. but not entirely, on the quality cf the basic trial257
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`.".'i“l!
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`”1
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`
`
`258
`
`Guarino
`
`Clinical Researt
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`design. Faulty execution. due e
`ither to sloppincss or tin rare instances) ills-
`honesty. can undermine the r
`aliditj.‘ and usefulness of the data generated from
`a particular trial site. All im-
`estigators and tiicir staffs must he meticul
`was in
`observing and reporting their clinical ohseri at ions. 0n the other hand.
`even it
`a lengthy trial is carried out with the utmost car
`c. the data generated will he
`useless if the protocol has not been dc
`signed intelligently. Overall.
`it must
`include all the necessary ingredi
`ents so that the eventual clinical results will
`support IND and NDA submis
`sions.
`Because the framework of
`every clinical research trial relies on a number
`of interdependent disciplines, the development of a clinical trial protocol is
`ideally a multidisciplinary task. Teamwork. C0t‘~l'tlltl;tl
`ed by one experienced
`person in clinical research with good knon ledge
`of the regulatory rc—
`quirements for new drug development. is essential. Tl
`should also include input. recommendations, and re\
`ie protocol design team
`'iew b}- the follmiting:
`A chemist who is tall} conversant with the
`physical and chemical
`properties of the investigational drug
`.~\ pharmacologisi and or toxicologist with a full understanding of the
`pharmacology and toxicology of the drug in animals and the expected ef—
`fective dose. therapeutic cfi't-cts. and possible adverse experiences in humans
`'
`ferably one who speciali
`'
`“
`
`ll. TRIAL 08‘
`
`A common fau
`
`trial. ObjCCllWl
`than one objECI
`fewer the quest
`that they will b<
`simplicity.
`
`Ill. GENERAL
`
`The trial protoc
`displays the elcn
`how the plan sh
`The proto<
`checklist similar
`Protocol: A Chi
`
`outline helps a \i
`speech. Judging
`for more clinica
`
`might assume th
`ingredients are n
`its presentation
`pleteness. and a
`In drug dex
`concise. straight
`their stalls. and
`
`drug developmei
`NDA review ant
`
`development. ar
`demonstrate efiit
`
`approval.
`
`IV. DIFFEREN
`
`Conventionally.
`the clinical inves
`
`Although the obj
`separate entities
`
`
`
`A statistician who will address those aspects of trial
`determine the form the trial data will take for an
`design that
`alysis and the types of
`analyses that will be applied to the data
`A data manage
`meat person who will be both involved in coding and in
`charge of data entry
`A potential investigator or consultant who understands the '
`to be researched and ti
`'
`'
`followed
`
`
`
`
`
`
`
`
`
`
`
`
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`
`
`
`
`-.»\ capable program in
`a nagcr who.
`can coordinate the mul
`effort to form a linal
`tidisciplinary
`protocnl and e
`tl‘ect practical execution in the clinical
`setting straight through to data analysis and final u rite-up
`’l‘ngcther. these specialists can prm ide hoth the criteri
`the trial and the I‘él tionale used to de\ elop them
`.‘ r
`a for all aspects of
`the protocol have been established. it is
`:astomar} for a protocol introduction
`to summarize these obicctiv
`es, give a brief overviex
`in the Investigators
`v ofthe information found
`Brochure (referencing the Brochure). and state the
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`Mylan V. Janssen (IPR2020-00440) EX. 1037, p. 005
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`Guaflno
`
`.nces) dis—
`aled from
`iculous in
`1d, even if
`ed will be
`i. it must
`asults will
`
`a number
`rotocol is
`
`perienced
`atory re—
`sign team
`lowing:
`chemical
`
`ng of the
`nected ef-
`; humans
`dition or
`:ticalities
`
`lign that
`types of
`
`1g and in
`
`tdiCfltiOl’l
`‘65 to be
`
`:iplinary
`: clinical
`
`spects of
`ctives of
`)duction
`,It found
`tate the
`used for
`clinical
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`Clinical Research Protocols
`
`259
`
`II. TRIAL OBJECTIVE
`
`A common fault in trial design is to have too many objectives in a single
`trial. Objective(s) should be clearly and concisely stated. If a trial has more
`than one objective, the objectives should be listed in order of priority. The
`fewer the questions to be answered in one trial, the greater the likelihood
`that they will be answered conclusively. The key to successful trial design is
`simplicity.
`
`III. GENERAL CONSIDERATIONS IN PROTOCOL DESIGN
`
`The trial protocol is the end point of research design. It is the blueprint that
`displays the elements of the trial plan and provides explicit instructions as to
`how the plan should be executed.
`The protocol designers should approach the subject by first organizing a
`checklist similar to the one presented later in this chapter (see Elements of a
`Protocol: A Checklist). This list will serve in protocol design much as an
`outline helps a writer or a speaker touch on all salient points in an article or
`speech. Judging from the number of NDAs that are returned to their sponsors
`for more clinical information (timc~consuming revisions) by the FDA, one
`might assume that there are tricks to the art of a successful filing. No secret
`ingredients are needed for the successful preparation of a clinical protocol or
`its presentation within an IND and ultimately the NDA—fiiust logic, com-
`pleteness. and a practical understanding of the disease under investigation.
`In drug development, time is of the essence. Clinical protocols should be
`concise, straightforward, and logical. The demands upon the investigators,
`their staffs, and the subjects must be reasonable. The FDA’s guidelines for
`drug development by disease must be considered in order to expedite the final
`NDA review and approval. The objective to remember throughout protocol
`development, and execution and presentation of the acquired data,
`is to
`demonstrate efficacy and safety to fulfill the FDA’s requirements for NDA
`approval.
`
`IV. DIFFERENT TRIAL DESIGNS
`
`Conventionally, phase I, 2, 3, 3b, and 4 trials refer to the successive stages of
`the clinical investigation of a drug or the continued experiment of the same.
`Although the objectives of all of the phases are diHerent, they are not entirely
`separate entities because the information obtained from one phase provides
`
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`.
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`‘ ”stunt
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`We
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`
`
`260
`
`Guarino
`
`Clinical Re
`
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`is a dem-
`the basis for the next. In broad terms, the objective of phase 1
`onstration of safety based on dose tolerance; phase 2 is for dose tolerance and
`safety balanced with efficacy (probably the most important phase in clinical
`research development); phase 3 reconfirms efficacy and safety in a larger
`subject population for a specified dose and indication in a target subject
`population; phase 3b is designed for large-scale safety. Phase 4 trials are
`usually classified as marketing trials and are designed to demonstrate how
`similar drugs, prescribed for the same indications, may show one having cer-
`tain advantages over another. The basic principles of good scientific methods
`of trial design apply equally to all five phases. The major tenets of all scientific
`experimentation should be regarded as fundamentals of the design: the
`possibility of coincidence as well as bias should be ruled out, and the results
`produced by the trial design should be as conclusive as possible. In other
`words, the trial should be controlled, designed, and analyzed for optimum
`statistical reliability and specificity.
`
`V. CONTROLLED TRIALS
`
`A trial drug can be compared with a placebo or with an active drug. If active
`medication is used as a control group, it should be a standard drug accepted in
`medical practice for the specific indication(s) under investigation. Double-
`blind trials are usually indicated to assure that the data obtained from these
`trials, when evaluated statistically, will support judgments regarding the
`safety and the efficacy of the investigational drug without bias. Because of
`ethical considerations, however, there are many drugs that cannot be eval-
`uated under double-blind conditions. In these cases, a sponsor should review
`the situation with the FDA and establish the acceptability of data to be
`obtained from a trial of alternate design before the trial has begun. It is not
`unusual, however, for phase 1 trials to be open-label (not blinded), because
`the objective is to observe the response to the investigational substance pri-
`marily in terms of safety.
`Double-blinded, controlled trials that are well designed yield the most
`valid results. In the majority of investigations, test agents are blinded against
`placebo controls. The FDA’s NDA approvals, in most cases, are based on the
`following:
`two clinical trials proving that a drug versus placebo shows
`statistically significant ditference. These are termed pivotal trials. Rare ex-
`ceptions are made, with active agents used as controls assumed to exert similar
`therapeutic conditions.
`Very rigid criteria are established to preclude investigator or subject
`bias. Impressions of drug efficacy or lack of the same based on previous eval-
`
`uations of
`of two or 1
`treatment:
`the treatm
`which asst
`variable (
`
`single-blin
`unaware (
`
`'
`method,
`comparat:
`subject ar
`administe
`
`A. Blint
`
`Attaining
`strict atte
`is necessa
`
`usually 51
`meet thes
`
`drugs in
`versus 51
`
`blinding
`including
`comparis
`
`ing impo
`dummy)
`istics. It
`
`test agen
`(Table 1:
`Ina
`simultan
`
`Table 1
`
`Group I
`
`Active D
`
`Placebo l
`
`
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`Mylan V. Janssen (IPR2020-00440) EX. 1037, p. 007
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`Clinical Research Protocols
`
`261
`
`nations of reported efficacy must be avoided. in a trial comparing the effects
`of two or more treatments, if the investigator or the subjects are aware of the
`treatments administered, the preconceptions and prejudices of both toward
`the treatments can have a significant biasing influence on the accuracy with
`which assessments of the clients of the treatments are made. This extraneous
`variable of bias can be minimized by suitable blinding tecltniquest The
`single—blind method. as the name implies. ensures that only the subject is
`unaware ol‘ the distribution of treatments during the trial. The double-blind
`method. which is now accepted as the standard blinding procedure in
`comparative drug trials. ensures that the investigators. their stalls, and the
`subject are unaware of the type of treatments that are being prescribed and
`administered.
`
`a
`
`A. Blinding Techniques
`Attaining and maintaining double~blind conditions in a clinical trial requires
`strict attention to a number of details. A drug form identical to the test drug
`is necessary for double-blind conditions. Pharmaceutical manufacturers can
`usually supply their products, placebo. and comparison drugs in forms that
`meet these requirements. Comparative evaluation trials cannot be done on
`drugs in dissimilar formulations. such as tablets versus syrups. ampules
`versus suppositories. or liquid concentrates versus capsules. Additional
`blinding problems are presented by variations in physical characteristics
`including colon taste. texture. viscosity. shape. or size. If a trial calls for the
`comparison ol‘ two treatments with formulations that make physical match-
`ing impossible. the problem can be solved by the double—placebo (double-
`dummy) method. which establishes manifest equality of product character-
`isticsl It consists of simultaneously administering to each subject an active
`test agent and a placebo of the other active agent that is being evaluated
`(Table 1)~
`Inasmuch as the two agents (whatever their forms) are administered
`simultaneously to each subject at all times during the trial, there is. no way of
`
`Table 1 Double-Placebo Method
`
`
`-;;.__
`-_
`Cf-
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`Ice and
`clinical
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`subject
`ials are
`ire how
`ing cer—
`methods
`cientific
`gn: the
`2 results
`it other
`ptimum
`
`If active
`:epted in
`Double-
`)m these
`ding the
`cause of
`be eval—
`,d review
`ta to be
`It is not
`,because
`ance pri-
`
`the most
`
`:1 against
`ed on the
`)0 shows
`Rare CX-
`:rt similar
`)1‘ subject
`.
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`Group 2 subjects
`Group 1 subjects
`‘ MActive Drug A tablets Active Drug B liquid
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`+ .
`+
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`Placebo A tablets
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`6% 9b
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`Mylan v. Janssen (IPR2020-00440) Ex. 1037, p. 008
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