Top Five Mistakes in Clinical Protocol Design

By Lisa R. Sanders, Ph.D., R.A.C., Sr. Clinical Scientist II at Cato Research

Almost a Holy Grail for the pharma/biotech world, the perfect clinical study protocol requires no amendments, collects only the data needed for the planned analysis, is fully feasible, and is enrolled on time. The reality is that the average clinical trial protocol requires 2-3 amendments (with >40% occurring before a subject is enrolled)[1], collects a large amount of data that is not associated with any key endpoint or regulatory requirement[2], and includes so many entry criteria that it can be almost impossible to enroll in a timely fashion. And while it is widely recognized in our industry that protocol design and complexity is a key cost driver, our industry struggles to make the changes necessary to address this issue.

Over the past 10 years as a clinical and regulatory scientist I have seen plenty of clinical study protocols from a lot of different companies: small virtual companies, medium-sized biotech companies with several products in the pipeline, and well-established global pharma with numerous marketed products. But regardless of company size or experience, there are protocol issues repeated again and again. Timelines, business pressures, egos, compartmentalization…all can contribute to a flawed clinical protocol. And since everything else flows from the protocol, issues are propagated down the line.  Here are the five mistakes I have seen most often and suggestions on how to mitigate them.

 

1. Too many objectives

A recent protocol I reviewed had nine different study objectives. Another had 20 (but to be fair, five were exploratory). As we try to pack more and more into a study as a cost saving measure, the number of objectives is increasing. The downstream affect is more endpoints and assessments, increased cost, more complicated logistics, and a muddled sample size determination and data analysis. Focus first on the key questions:

  • Why do I need this study?
  • What is the primary scientific question I need to answer?
  • What are the regulatory requirements that must be met by this study?
  • What must I learn to support the next step in development?

This gives the basis for the handful of objectives your study will support. To keep your protocol focused, at Cato Research we recommend no more than 1-2 (preferably 1) major/primary objectives and no more than 3 minor/secondary objectives.

 

2. Not first creating clear, concise, well written, and agreed on objectives

All too often we see protocol objectives that are too broad, unclear, or missing key information. For example: “To determine the safety and tolerability of Drug X.” So broad an objective does not give us much to work with to determine endpoints, assessments, and design the data analysis.

A well written objective will include all of the following information:

  • Product being tested
  • Dosing: level(s), frequency, duration, and mode of administration
  • Study population
  • Clinical endpoint
  • Parameter measured
  • Time of assessment
  • Control

Adding to our previous example: The primary objective of Study CLIN-002 is to evaluate the safety and tolerability of Drug X capsules at four dose levels (5 mg, 10 mg, 15 mg, 20 mg), versus placebo, when administered orally once daily for 28 days to subjects with hyperlipidemia by assessing adverse events, physical examinations and vital signs, 12‑lead electrocardiogram, clinical blood chemistries, hematology, and urinalysis during the treatment period.

A specific objective such as this provides clear direction for your endpoints, assessments, and statistical analysis. You can be sure the data collected will evaluate the specific question you are trying to answer. And your objectives require input from others BEFORE they are finalized (see Step 3).

 

3. Not seeking interdisciplinary input (a.k.a., Not enough cooks in the kitchen)

A clinical protocol merges scientific data, medical expertise, regulatory requirements, and operational logistics. But all too often medical writers go it alone in the protocol development process, and only look for input on the final product, when substantive changes are time consuming and often shunned. And input from the clinical operations perspective can be overlooked entirely. Interdisciplinary input is key from the start of what is a three-stage process:

  • Objectives and endpoints: Input from medical experts and statisticians at the objective stage is key to ensure they can be supported by measurable, collectable, and analyzable endpoints. Regulatory input is needed to ensure that data required by regulatory authorities is not overlooked. An interdisciplinary review of the study objectives and their supporting endpoints at this stage is a must.
  • Synopsis: Creation of the study synopsis through the addition of logistical and data collection, and data analysis details requires input from medical, data management, statistics, and clinical operations. This ensures your protocol design meets applicable guidelines, is logistically sound, and produces analyzable data before all the body text is added. Again, interdisciplinary review and agreement is critical at this stage, while your protocol is still in outline form.
  • Full protocol: Armed with a fully vetted synopsis, creating the full protocol basically becomes a “fill in the blank” exercise. The key design decisions are behind you, and you can proceed knowing it is unlikely there will be many surprises during the final review process.

At Cato Research, we plan an interdisciplinary round table meeting at each stage of the protocol development process. This provides an efficient approach to garner interdisciplinary input that allows discussion and consensus among the different disciplines.

 

4. Just doing what you (or someone else) did last time

 It is not unusual to do a protocol review and find some entry criteria, endpoints, or assessments that just do not make sense in the context of the study. For example, having a criteria that prohibits pregnancy or breast feeding in a congenital hemophilia or dementia study. And when we ask where an item came from, it is not uncommon to hear, “That was included in other protocols I looked at,” or “That was in the last protocol we ran in this indication.”

It can make a lot of sense to go back and look at what you did last time–why reinvent the wheel, right? A review of published studies and those active in clinicaltrials.gov can provide insight into current design trends for a specific indication. Your last protocol for Disease X was thoroughly reviewed and successfully run, so it may be a good starting point. But over time and across authors, the specific reasons why a certain endpoint or entry criterion was included can be lost. The study population is different, the indication has changed, the “gold standard” endpoint has changed, the statistical approaches have evolved. Exercise caution when following the example of earlier protocols. Critically evaluate the basic design elements to ensure they still apply. And do not skimp on Step 3 just because you had an example to start with.

 

5. Redundancy, Repetition, Reiteration

 Call it what you will, but repeating the same thing in multiple sections of a protocol can create serious headaches. Consider the following four examples of protocol text from four different sections of a single protocol (synopsis, methodology, time and events table, and protocol body, respectively):

  • Vital signs including pulse, blood pressure, and respiratory rate will be routinely monitored during treatment, minimally at each assessment.
  • Vital signs will be collected 10 minutes after administration of dose
  • Vital signs (10-20 minutes after administration of dose), includes blood pressure, heart rate, respiratory rate, temperature
  • Vital signs are taken at each dose

Sites may follow different timing for vital sign collection, based on where in the protocol they are looking. Vitals could be taken at the time of the dose, between 10 and 20 minutes after dosing, at 20 minutes after dosing, and some sites will not include temperature. While this could be considered a minor problem in this example, it provides an excellent illustration of what can happen when the same detail is repeated in multiple protocol sections. Throw protocol amendments into the mix and you can end up with a mess.

So how do we fix this? Simple–eliminate repetition of details wherever possible.

  • Keep the synopsis and methodology sections to a high level descriptions and put the details in the protocol body text. Refer to specific sections if needed.
  • Avoid footnotes in a time and events table, and instead reference the appropriate protocol section or a study procedures manual.
  • Consider developing standardized template text to be used across protocols for common, recurrent items such as the assessment of physical health, medical history, concomitant medications, adverse events, and blood and urine collections.
  • Whenever possible, you can keep the nitty gritty (e.g., collection time windows, study product logistics) out of the protocol and in a separate study procedures manual. This also eliminates the need to amend the protocol for minor procedural changes.
  • Review, review, and review (see Step 3). Getting fresh eyes on the final protocol is a great way to catch inaccuracies and repetition.

There is often a great deal of pressure to author a protocol quickly to meet a filing deadline, a corporate milestone, or to keep development moving forward quickly. But protocol amendments are costly and time consuming to produce and implement. Having from the outset a concise, well-written, substantively designed, logistically feasible protocol that minimizes amendments will more than make up for the additional up front time.

 

[1] http://csdd.tufts.edu/news/complete_story/pr_ir_sep-oct_2011 (accessed 25 Sep 14)

[2] http://csdd.tufts.edu/news/complete_story/pr_ir_sep_oct_2014 (accessed 25 Sep 14)

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New FDA Guidances for September 2014

By Sheila R. Plant, Ph.D., R.A.C., Regulatory Scientist at Cato Research
FDA draft and final guidances, released from CDER, CBER, and CDRH in September, are posted. In addition, upcoming advisory committee meetings and other public meetings hosted by FDA are listed below with links to more information.

Special Interest Guidances/Information Date Posted
ANDA Submissions — Refuse-to-Receive Standards – Final Guidance 16 Sep 2014
ANDA Submissions — Refuse to Receive for Lack of Proper Justification of Impurity Limits – Draft Guidance 16 Sep 2014
Guidance for Industry: Recommendations for Screening, Testing, and Management of Blood Donors and Blood and Blood Components Based on Screening Tests for Syphilis- Final Guidance 03 Sep 2014
CDER Manual of Policies & Procedures, Drug Shortage Management - 04 Sep 2014
Content and Format for Abbreviated 510(k)s for Early Growth Response 1 (EGR1) Gene Fluorescence In-Situ Hybridization (FISH) Test System for Specimen Characterization Devices – Draft Guidance 26 Sep 2014
Policy Clarification for Certain Fluoroscopic Equipment Requirements – Draft Guidance 25 Sep 2014
Custom Device Exemption - Final Guidance 24 Sep 2014
Class II Special Controls Guideline: Tryptase Test System as an Aid in the Diagnosis of Systemic Mastocytosis – Guideline for Industry and Food and Drug Administration Staff – Final Guidance 18 Sep 2014
Class II Special Controls Guideline: Dengue Virus Nucleic Acid Amplification Test Reagents – Guideline for Industry and Food and Drug Administration Staff- Final Guidance 10 Sep 2014
Upcoming Meetings (* = New)
 

*

Circulatory System Devices Panel of the Medical Devices Advisory Committee Meeting; 8-9 Oct 2014; Gaithersburg, MD
Joint Meeting of the Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting; 16 Oct2014, Silver Spring, MD
Dermatologic and Ophthalmic Drugs Advisory Committee Meeting; 20 Oct 2014; Silver Spring, MD
 

*

Cardiovascular and Renal Drugs Advisory Committee Meeting; 30 Oct 2014; Silver Spring, MD
Cellular, Tissue and Gene Therapies Advisory Committee Meeting;06 Nov 2014; Silver Spring, MD
 

*

Orthopaedic and Rehabilitation Devices Panel of the Medical Devices Advisory Committee Meeting; 12 Dec 2014; College Park, MD
Food Advisory Committee Meeting ; 16-17 Dec 2014; Silver Spring, MD; Silver Spring, MD

* new entry

Last updated: 02Oct 2014

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Drug Master Files (DMFs) in the United States, Canada, and European Union

By Amy S. Blawas, Ph.D., R.A.C., Associate Director of Pharmaceutical Development, Senior Scientist Cato Research Ltd.

Recently, Cato Research has experienced an increased client activity in filing and maintaining Drug Master Files (DMFs) in the United States, Canada, and European Union. DMFs are a voluntary means for a contract manufacturer or supplier of an active pharmaceutical ingredient (API), an excipient, or packaging to submit information to the Food and Drug Administration (FDA) while protecting their intellectual property. Although not required from a regulatory standpoint, a DMF allows detailed information about facilities, processes, or materials used in the manufacturing, processing, or packaging and storing of human drugs, biologics, and devices to be submitted in support of an application while maintaining confidentiality. A description of the contents of a US DMF is provided in the Code of Federal Regulations, 21 CFR 314.420, and explained in the September 1989, Center for Drug Evaluation and Research (CDER) Guideline for Drug Master Files. Unlike European and Canadian master files, all parts of a US DMF are ‘open’ only to the FDA for review and remain ‘closed’ to the applicant referencing the DMF in their application.

There are five types of US DMFs:

  • Type I: Manufacturing site, Facilities, Operating Procedures, and Personnel
  • Type II: Drug Substance, Drug Substance Intermediate, and Material Used in their Preparation or Drug Product
  • Type III: Packaging material
  • Type IV: Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation
  • Type V: FDA Accepted Reference Information

As of June 12, 2000, Type I files are no longer accepted by the FDA, although some Type I DMFs are still active. Currently, DMFs are primarily structured according to the format and granularity described in the International Conference of Harmonization-Common Technical Document. A pre-assigned DMF number is required for an electronic DMF submission and is also recommended for a paper DMF submission. Additional requirements for DMFs under the Generic Drug User Fee Amendments (GDUFA) of 2012, including payment of the DMF fee are described in guidance documents available on the FDA/CDER website.

Upon submission, a DMF is not approved or disapproved, but reviewed for completeness. The DMF holder must issue a letter of authorization (LOA) for the FDA to access and review the technical contents of the DMF in support of an application. This LOA is submitted to the DMF and sent to the applicant who wishes to reference the DMF in support of their filing.   Based on the subsequent submission of an Investigational New Drug application (IND), a New Drug Application (NDA), an Abbreviated New Drug Application (ANDA), an Export Application, or amendments or supplements to any of these submissions, containing the LOA, the FDA will review the DMF contents as connected to that application.

In addition, DMFs can be submitted for Biologics products. Specifically, biologics contract manufacturing facilities can file Type V Master Files involving proprietary information that should include all products manufactured at the facility and any non-compendial test procedures. Master File documentation can be submitted to the FDA to support medical device applications, and this submission is called a Master File for Devices (MAF).

DMFs have their own regulatory requirements in order to remain current and accessible. Once filed, DMFs require an annual report due on the anniversary date of the submission that includes a list of all parties authorized to access the DMF, and all changes and additions to information in the DMF. If an annual report is not submitted for three years, the DMF holder will be notified with an overdue notification, and after 90 days the DMF will be closed. In addition, amendments can be submitted to the DMF to report changes, deletions, or additions of administrative or technical information.

 

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New FDA Guidances for August 2014

By Sheila R. Plant, Ph.D., R.A.C., Regulatory Scientist at Cato Research
FDA draft and final guidances, released from CDER, CBER, and CDRH in August, are posted. In addition, upcoming advisory committee meetings and other public meetings hosted by FDA are listed below with links to more information.

Special Interest Guidances/Information Date Posted
Recommendations for Screening, Testing, and Management of Blood Donors and Blood and Blood Components Based on Screening Tests for Syphilis – Final Guidance 29 Aug 2014
Electronic Submission of Lot Distribution Reports- Draft Guidance 29 Aug 2014
Controlled Correspondence Related to Generic Drug Development- Draft Guidance 26 Aug 2014
Evaluation of Sex-Specific Data in Medical Device Clinical Studies – Final Guidance 22 Aug 2014
Unique Device Identifier System: Frequently Asked Questions, Vol. 1 -Final Guidance 20 Aug 2014
FDA Decisions for Investigational Device Exemption Clinical Investigations – Final Guidance 19 Aug 2014
De Novo Classification Process (Evaluation of Automatic Class III Designation) - Draft Guidance 14 Aug 2014
Clinical Pharmacology Labeling for Human Prescription Drug and Biological Products—Considerations, Content and Format – Draft Guidance 13 Aug 2014
Immunogenicity Assessment for Therapeutic Protein Products - Final Guidance 13 Aug 2014
Unique Device Identification System: Small Entity Compliance Guide – Draft Guidance 13 Aug 2014
Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act – Draft Guidance Aug 2014
In Vitro Companion Diagnostic Devices – Final Guidance 06 Aug 2014
Design Considerations for Devices Intended for Home Use- Final Guidance 05 Aug 2014
Upper Facial Lines: Developing Botulinum Toxin Drug Products - Draft Guidance 05 Aug 2014
Recommendations for Donor Questioning, Deferral, Reentry and Product Management to Reduce the Risk of Transfusion-Transmitted Malaria – Final Guidance 01 Aug 2014
FY 2015 Medical Device User Fee Small Business Qualification and Certification – Final Guidance 01 Aug 2014
Intent to Exempt Certain Class II and Class I Reserved Medical Devices from Premarket Notification Requirements – Draft Guidance 01 Aug 2014
Upcoming Meetings (* = New)
Cardiovascular and Renal Drugs Advisory Committee Meeting; 10 Sep 2014; Silver Spring, MD
Methodological Considerations in Evaluation of Cancer as an Adverse Outcome Associated With Use of Non-Oncological Drugs and Biological Products in the Postapproval Setting; Public Meeting; Request for Comments; 10-11 Sep 2014; Silver Spring, MD
Endocrinologic and Metabolic Drugs Advisory Committee Meeting; 12 Sep 2014; Hyattsville, MD
Joint Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee; 17-18 Sep 2014; Hyattsville, MD
Meeting of the Pediatric Advisory Committee, 23 Sep 2014; Bethesda, MD
Joint Meeting of the Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting; 16 Oct2014, Silver Spring, MD
* Dermatologic and Ophthalmic Drugs Advisory Committee Meeting; 20 Oct 2014; Silver Spring, MD
* Cellular, Tissue and Gene Therapies Advisory Committee Meeting;06 Nov 2014; Silver Spring, MD
* Food Advisory Committee Meeting ; 16-17 Dec 2014; Silver Spring, MD; Silver Spring, MD

* new entry

Last updated: 2Sep 2014

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New FDA Guidances for July 2014

By Sheila R. Plant, Ph.D., R.A.C., Regulatory Scientist at Cato Research

FDA draft and final guidances, released from CDER, CBER, and CDRH in July, are posted. In addition, upcoming Advisory committee meetings and other public meetings hosted by FDA are listed below with links to more information.

Special Interest Guidances/Information Date Posted
In Vitro Companion Diagnostic Devices – Final Guidance 31 July 2014
Center for Devices and Radiological Health Appeals Processes: Questions and Answers About 517A – Final Guidance 30 July 2014
The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)] - Final Guidance 28 July 2014
Providing Submissions in Electronic Format — Postmarketing Safety Reports for Vaccines – Draft Guidance 18 July 2014
Benefit-Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications [510(k)] with Different Technological Characteristics -Draft Guidance 15 July 2014
Informed Consent Information Sheet – Draft Guidance 15 July 2014
ANDA Submissions – Prior Approval Supplements Under GDUFA - Draft Guidance 10 July 2014
ANDA Submissions – Amendments and Easily Correctable Deficiencies Under GDUFA -Draft Guidance 10 July 2014
Design and Analysis of Shedding Studies for Virus or Bacteria-Based Gene Therapy and Oncolytic Products – Draft Guidance 09 July 2014
Neglected Tropical Diseases of the Developing World: Developing Drugs for Treatment or Prevention - Final Guidance 03 July 2014
Current Good Manufacturing Practice — Interim Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act - Draft Guidance 01 July 2014
Pharmacy Compounding of Human Drug Products Under Section 503A of the Federal Food, Drug, and Cosmetic Act – Final Guidance 01 July 2014
Upcoming Meetings (* = New)
Confidentiality of Interim Results in Cardiovascular (CV) Outcomes Safety Trials; Part 15 – Public Hearing Before The Commissioner; Request for Comments; 11 Aug 2014; Silver Spring, MD
* Pulmonary-Allergy Drugs Advisory Committee Meeting; 14 Aug 2014; Silver Spring, MD
Cardiovascular and Renal Drugs Advisory Committee Meeting; 10 Sep 2014; Silver Spring, MD
* Methodological Considerations in Evaluation of Cancer as an Adverse Outcome Associated With Use of Non-Oncological Drugs and Biological Products in the Postapproval Setting; Public Meeting; Request for Comments; 10-11 Sep 2014; Silver Spring, MD
* Endocrinologic and Metabolic Drugs Advisory Committee Meeting; 12 Sep 2014; Hyattsville, MD
* Joint Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee; 17-18 Sep 2014; Hyattsville, MD
* Meeting of the Pediatric Advisory Committee, 23 Sep 2014; Bethesda, MD
Joint Meeting of the Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting; 16 Oct2014, Silver Spring, MD

* new entry

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