Clinical Submissions That Qualify for 505(b)(2) Approval

The purpose of FDA Section 505(b)(2) of the Hatch-Waxman Act is intended to promote and approve investigational medications that are safe and efficacious, novel therapeutics, while saving cost, time, resources and avoiding unnecessary duplication of clinical efforts and patient exposure, human testing. Clinical submissions for investigational medications that qualify for 505(b)(2) application and approval are, but are not limited to:

• Change in dose
• Change in dosage form
• Change in excipient
• Change in formulation
• Change in the route of administration
• Change in mechanism of action
• Change in prescription combination drug
• Change in physical, chemical structure
• Change in regimen
• Change in protocol
• Change in origin or parent compound
• Change in how derived, natural, recombinant, proteomic, genomic, for examples
• Change in OTC combination drug
• Change in delivery, transdermal, capsule, device, inhalation, for examples
• Change in strength
• Change in active ingredient
• Change in therapeutic indices or indications.

Approving 505(b)(2) clinical submissions and medications have been challenged by pharmaceutical companies, drug manufacturers, citizen groups and physicians, from a competitive view and challenging to FDA and worldwide regulatory agencies pertaining to accelerated review.

The 505(b)(2) process allows the applicant to utilize previously submitted information from an already approved medication. As well, the applicant is allowed to use literature, post-marketing prescribing safety information, SAE reports and FDA's prior findings of safety, effectiveness, tolerance, pharmacologic and pharmacokinetic of an approved medication at filing. Remember, for the NDA to be considered as a 505(b)(2) candidate for approval, some portion of the information submitted for approval must come from sources other than studies performed by the applicant. If the applicant has obtained the right of reference to the information, a 505(b)(1) application and clinical submission must be submitted instead. The 505(b)(2) process can no longer be used and in fact, if used, the submitter will receive a Refusal to File. The requirements for 505(b)(1) and 505(b)(2) are basically the same with several differences. The right of reference is the an important, major difference between the two regulatory pathways to approval. For accurate, comprehensive, up to date regulatory and clinical submission consultation contactus@danteresources.com, danteresources@yahoo.com.

Approval Under FDA Clinical Submission - Regulatory Section 505(b)(2)

Drug products filed with FDA for clinical submission and marketing approval under Section 505(b)(2) are not new products, but are products that already have an active ingredient previously approved by a regulatory agency or is now formulated differently, or has a different route of administration, or will show safety and effectiveness in a different therapeutic indication or demonstrates a different mechanism of action. The appropriate regulatory pathway for either consideration above is to seek marketing approval via FDA 505(b)(2).

The active ingredient has certain information already known about the active ingredient, thus an abbreviated application and clinical submission process that does not require extensive testing via the NDA new drug route of regulatory approval is the chosen path. With a "new" NDA, FDA requires complete extensive clinical trials, Phase 1, 2 and 3. Phase 1 clinical trials involve a small number of healthy volunteers. The basis of the clinical Phase 1 program is to ascertain the pharmacologic and pharmacokinetic activity and tolerance of the drug in humans. The Phase 2 clinical program examines preliminary data in a small number of humans related to the medication's effectiveness, safety, adverse event profile, risk/benefit in patients with a diagnosed disease, a therapeutic indication. The Phase 3 clinical program is extensive, involving a large number, several thousand patients or more participating to evaluate the safety, efficacy and overall risk/benefit ratio for use of this medical product in the general population.

Under the rules in Section 505(b)(2), the applicant can rely on information from clinical studies it did not conduct, but were previously approved by FDA. Thus the 505(b)(2) pathway is considered an abbreviated approach to a "NDA", cost effective, with reduced time to approval and market. The 505(b)(2) application requires full clinical study reports of investigations of safety and efficacy where at least some portion of the information submitted for approval comes from studies submitted for previous approval. The applicant can rely for example, on literature describing the safety, effectiveness, risk/benefit, adverse event profile. The applicant will have FDA's findings of safety and effectiveness from the previous approved medication. As well, pharmaco-safety data and prescribing information are available and must contribute to the clinical submission 505(b)(2) approval process.

Remember, previously submitted, FDA approved clinical submission data and documentation has been quality-controlled and quality assured. It is a must that new clinical data and documentation submitted in the 505(b)(2) filing be consistent with scientific, clinical and statistical statements, data and documentation previously approved. A quality control or QC review to compare previously submitted materials and "to be filed" new clinical data and documentation is a must. This includes post marketing safety data and documentation. Clinical submission data and documentation, collected worldwide fall into the QC cycle. If QC is not applied or utilized, the end result is a disaster (impacting new and previously approved products) and results in data inconsistency and a Refusal to File with FDA, for starters. For QC review contactus@danteresources.com, danteresources@yahoo.com.

FDA - Inspections, Compliance, Enforcement and Criminal Investigations

In 2010, a noted increase is observed in warning letters issued to pharmaceutical sponsors regarding Form FDA 483 and Investigational Device Exemptions (IDEs). The warning letters were issued by FDA to inform the the pharma sponsors of objectionable conditions observed during a FDA for cause, onsite investigation at selected clinical sites. The purpose of a 483 inspection is to determine whether the activities of the pharmaceutical sponsor/clinical investigator at clinical investigative sites comply with applicable federal regulations. A trend of increasing serious violations of Title 21, CFR Part 812, IDE was noted by FDA inspectors during unannounced onsite inspections. Inspections by FDA investigators are conducted under a regulatory program designed to ensure that data and documentation contained in requests for IDE and PMA applications, approvals and 510(k) clinical submissions are scientifically valid and accurate. Another objective of the FDA program is to ensure that human subjects are protected from undue safety hazard or risk during the course of scientific/clinical study investigations.

Most common violations issued by FDA during onsite inspections:

• failure to obtain FDA approval prior to allowing subject participation in a clinical investigation
• failure to ensure adequate monitoring
• failure to complete Form FDA 1572
• failure to complete Subject Informed Consent
• failure to obtain IRB approval
• failure to obtain a signed agreement from each clinical investigator that includes sufficient accurate financial disclosure
• failure to submit complete and accurate clinical investigator certification and study disclosure statements
• failure to qualify clinical investigators
• failure to qualify clinical investigation sites.

Numerous violations were observed during inspections relating to adequate, quality and management at the clinical investigation sites. Sponsors are responsible for ensuring proper monitoring of the investigation and collection of data and documentation. Most common "monitoring" violations observed, but not limited to:

• Standard Operating Procedures (SOPs)
• Clinical Study Monitoring Procedure
• Monitoring Visit Reports - omissions, missing laboratory tests, missing evaluations, missing conditioning logs, missing diaries
• Monitoring Visit Reports - inc0mplete and inaccurate subject CRF
• Monitoring Visit Reports - inaccurate, missing subject notes, copies of evaluations and exams.

The monitoring reports were noted to lack documentation for corrections and/or clarifications for the cited omissions. Immediate response from the pharmaceutical sponsor is required and expected. Within 15 working days of receiving such warning letters from FDA, it is required and expected that the pharmaceutical sponsor provide written documentation of actions taken, or to be taken to correct violations and prevent the recurrence of similar violations in current or future studies for which the pharmaceutical sponsor is involved. A corrective action plan must be submitted. The plan must be comprehensive and include projected dates of completion for each corrective action. Failure to comply and response is not recommended.

Monitor, monitor, monitor. QC data and documentation. QC process, GCP and compliance. QC SOPs and implementation at each investigation site. Review regulatory requirements contactus@danteresources.com, danteresources@yahoo.com.

FDA IVDMIA Rule, PMA, 510(k) Application and Clinical Submission

Often discussed today, is the delay by FDA on its final rule on In Vitro Multi-Variant Index Assays (IVDMIAs). The delay is mainly due to a request by the Office of Management and Budget. The delay will impact IVDMIA development, regulatory rigor and review, guidance, requirements and clinical submission via PMA, 501(k) and otherwise. In 2007, FDA released a draft guidance to the industry pertaining to governance, compliance, safety, effectiveness, substantial and certifiable equivalence. Since July 2007, numerous discussions, forums, conferences, working sessions with FDA and interested groups have taken place with best efforts to resolve FDA concerns pertaining to high risk to patient safety. The delay of course in the past 3 years have impacted companies that are application and clinical submission ready with go-to-market IVDMIA strategies and final image products and kits.

The delay, uncertainty and concern of FDA has slowed investor participation. Uncertain of regulatory rigor, requirements and thus timelines and costs, investors are shy to invest. ROI is uncertain. Approvals are uncertain. Pre- and post-market guided enforcements, surveillance and commitments by FDA involving IVDMIA are uncertain. Best efforts to release a final rule by FDA with interested parties in 2009-2010 are ongoing. Currently circulating since March 2010, is a "notice of proposed rulemaking" from FDA for IVDMIAs. The process allows a 60 day public comment, review and appeal period followed by a 30 day period for FDA, government response. Interested parties are hopeful for a final rule from FDA June 2010. Not likely. Maybe end of summer 2010, maybe end of year 2010. FDA's concerns are but not limited to:

• high risk to patient safety
• product effectiveness
• product validity
• clinical validation
• clinical outcome determination
• clinical diagnosis
• clinical interpretation
• product surveillance, pre- and post-market
• regulatory enforcements, requirements and guidance
• complicated, complex diagnostic array platforms
• molecular and proteomic complexity
• observation correlations between multivariate data and clinical outcome
• IVDMIA considered a unique device, case by case
• how to regulate IVDMIA devices to ensure a safe and effective intended use
• patient reliance upon IVDMIAs with high risk diagnosis
• patient reliance upon IVDMIAs and intended use to make health care decisions when FDA has not ensured that the IVDMIA has been clinically validated.

In the most current draft guidance, FDA emphasizes additional enforcement discretion. FDA considers IVDMIAs of high risk intended use since they include elements that are more complex than standard CLIA/LDTs and include unique interpretation functions that cannot be independently validated by clinicians. FDA seeks to identify and measure IVDMIAs as a discrete category of device. Companies must meet pre- and post-market device requirements under the Federal Food, Drug and Cosmetic Act and FDA regulations, including pre-market review requirements following Class II and Class III devices. Regulatory rigor and review, quality control, quality assurance, clinical interpretation of accurate, normal range determinations, false positive and false negative samples are a must. Quality process and management plans are a must. High quality sample and testing data is a must. For innovative development, application, 510(k), PMA clinical submission, FDA communication, quality data and monitored, project-lead and managed development contactus@danteresources.com, danteresources@yahoo.com.

FDA Form 1572 and Information Sheet Guidance May 2010

The FDA form 1572 is a form that must be completed by clinical investigators worldwide prior to their participation in FDA-regulated clinical trials. Many clinical investigators, sponsor pharmaceutical companies and monitors still may not appreciate the growing complexities involved in completing the mandatory form, implications
of non-compliance or clinical submission. Last year, FDA issued numerous warning letters due to failure to complete and/or failure to file. Experienced clinical investigators continue to struggle with 1572 issues pertaining to:

• satellite clinical sites
• dispersion of study functions
• qualifications
• sub-investigator
• co-investigator
• legal/regulatory implications
• legal contract considerations
• appropriate expert standards
• country-specific uses
• collection of source documentations and process.

Offered at http://www.danteresources.com/ are the following pdf files for your download, information and use. Just released and published in May 2010, FDA offers a comprehensive, 17 page guidance on process, procedure, quality and otherwise for:

• FDA Form 1572 - Statement of Investigators - Title 21 CFR Part 312.53(c)
• FDA Form 1572 Information Sheet Guidance for Sponsors, Clinical Investigators and IRBs and Frequently Asked Questions.

Available at druginfo@fda.hhs.gov. Published May 2010, US Department of Health and Human Services, FDA, Office of GCP, CDER, CBER, Procedural Recommendations.

Who should read the guidance and understand the form? Clinical trials monitors, clinical investigators, site staff, research center compliance officers, CRC, CRA, QC, QA, IRB, CSTM, Regulatory Affairs Staff, Pharmaceutical Sponsors. Form FDA 1572 issues will trigger a Refusal to File, RTF as well.

FDA Action and Enforcement Involving Medical Product Misbranding

FDA closely monitors the development, performance, safety and efficacy of drugs, diagnostics, biologics, personalized, combination, traditional, proteomics, genomics and delivery device systems as well as investigating illegal actions involving Internet "website" misbranding of drugs, claims, marketing, sales initiatives, advertising and otherwise. In 2009, for example, FDA coordinated a week long, global effort to uncover such illegal activities. Via the IIWA, FDA issued at least 22 warning letters pertaining to "website" illegal claim and misbranding activities involving:

• service providers
• domain name registrars
• selling products violators
• prescription drugs
• pharmacies
• counterfeit drugs
• contaminated drugs
• expired drugs
• adulterated drugs
• unapproved drugs
• active ingredient inconsistencies
• change of formulation
• batch to batch, lot to lot deviations
• CMC changes
• counterfeit claims
• altered medical devices.

Divisions at FDA working in conjunction with FDA's OCI, Office of Criminal Investigation, CDER, Center for Drug Evaluation and Research, Office of Regulatory Affairs, targeted 136 websites who were actively and knowingly engaged in the marketing and sale of unapproved and/or misbranded medical products and drugs. The penalties for such illegal actions are civil and criminal, resulting in imprisonment, fines, immediate company closure, loss of operating licenses and otherwise. The violations trigger immediate loss of service provider and domain name registrars, revocation, suspension and termination. Seizure and elimination of the illegal supply chain, drug, medical products and devices are immediate. The protection is enforced due to the medical risk and danger to patients and consumers trusting false, misleading, misbranded, illegal claims for profit.

The initiative was sponsored by the ICPO, International Criminal Police Organization, the World Health Organization's International Medical Products Anti-Counterfeiting Task Force, the Permanent Forum on International Pharmaceutical Crime and national health and law enforcement agencies from 24 participating countries. Immigration, Customs, Border Protection, US Postal and other government worldwide agencies were involved in the week long effort to curb civil and criminal "misbranding" activities.

Information pertaining to the warning letters issued by FDA pertaining to the information cited above may be found on fda.gov.

Monitor the quality, consistency, accuracy pertaining to branding and labels, claims. Adhere to agency compliance and meet regulatory requirements for all phases of medical product development, preclinical, CMC, clinical, application, implementation, surveillance, clinical submission, pre-approval, approval, post-approval commitments, advertising, marketing, branding, label requirements, claim substantiation and sales.

QC, QC and QC again. Monitor, monitor and monitor again. contactus@danteresources.com.

Proteomic Discovery, Development, Clinical Submission - From Peptides to Biomarkers

Among new, emerging discoveries, personalized medicine, combination products, delivery systems, translational medicine is the discovery of peptide biomarkers, proteomics. Biomarker discovery is a dynamic area of R&D which is born from natural, native physiological and pathological processes in biological systems. The field of biomarker discovery and development - identification, classification, R&D, clinical development phase, transition and validation is currently under debate. A number of groups such as NIH, National Institute of Health Biomarker Definitions Working Group, Divisions at FDA and other regulatory agencies worldwide are in the process of establishing set criteria for proteomic biomarker development.

There are 3 types of Biomarkers:

• Prognostic: capable of providing information on clinical outcome at the time of diagnosis, independent of therapy
• Predictive: capable of providing information on the likelihood of response to a given therapeutic modality
• Screening: capable of providing information on clinical diagnosis in the general population.

The developmental phases are commonly categorized as Discovery, Transition and Validation.

Estimated timelines for the development of a proteomic biomarker (total duration = 48 months) is provided in months:

• Discovery 14
• Prototype Assay Development 5
• Pre-Validation of Assay 5
• Assay Development 7
• Clinical Validation 17.
• Clinical Validation includes, 5 phases of development - preclinical, Phase 1,2,3,4.
• The number of samples that must be collected and tested from discovery through validation into application and implementation increase in size in late phase development. Preclinical, POC, Proof of Concept samples collected and tested are usually small in number in discovery = 10, reaching hundreds in the validation stage, transitioning to thousands by the time of application to FDA and implementation.

Regardless of the type, a biomarker must demonstrate, under routine implementation methodologies and conditions of use how the marker impacts clinical management of a patient with life-threatening or terminal disease, either by improving patient outcome or QoL, Quality of Life or by lowering cost and time of patient care.

The quality, accuracy, reproducibility, consistency and integrity of data must be of high level and must be quality controlled, processed and assured. Quality management plans, SOPs, WIs, GCP, GLP, GMP and otherwise must be developed and meet compliance quality standards. All plans, procedures and processes must be developed in accordance with FDA regulatory requirements, guidance and guidelines for the year of the application/implementation. contactus@danteresources.com, danteresources@yahoo.com.