Differences in EU and US 510(k) Market Approval

Often asked by sponsor pharma and medical device manufacturers - is there a difference in clinical criteria and regulatory submission requirements? Differences in Class II and Class III medical device 510(k) regulatory clearance processes do exist. In particular is the process pertaining to issuance for a 510(k) medical device CE Mark. The EU CE Mark process requires medical device demonstration of safety only, and not efficacy and relies heavily on non-governmental opinion leaders or "Notified Bodies (NBs)" to regulate acceptance criteria, regulatory process, approval registration and post-approval post marketing surveillance for safety. In contrast, approval in the US of a new moderate to high risk Class II or Class III medical device requires demonstration of both safety and efficacy and is more regulated by a central governmental agency, CDRH/FDA. European Union Member Countries most often utilize CE review and approval from NBs, particularly because there is a huge savings in clinical development and clinical submission costs and thus time, with shorten timelines to registration and marketed medical device. Remember, EU approval is based only on data and documentation relating to safety and thus the NBs are often seen and chosen as a quick outlet to success and market CE approval. NBs can issue the CE Mark, they are independent, commercial organizations which implement regulatory control, monitor performance and safety of EU approved Class II or Class III medical devices.

NBs:

• review
• monitor
• audit
• critique medical device design
• assess safety
• verify quality systems
• review clinical submission data and documentation
• guide regulatory process
• approve medical devices
• issue CE Marks
• establish EU post marketing safety surveillance programs
• regulate country-specific requirements and governance.

A medical device sponsor or manufacturer is free to choose an NB within the European Union. Within the European Union, there are more than 50 active NBs to date currently reviewing CE applications and registrations.

In the US, a 510(k) application is submitted to CRDH/FDA. The medical device must be safe and efficacious. The 510(k) application typically requires prospective, randomized, controlled clinical trials. To receive clearance from CDRH/FDA, clinical trial results must demonstrate safety, performance and efficacy, significantly demonstrate acceptable intended use. Clinical trials supporting a Class II or Class III medical device 510(k):

• includes ~800 patients
• multi-center
• randomized
• controlled
• comparative.

A typical clinical trial including 800 patients with the above bulleted design criteria will cost the medical device sponsor or manufacturer 10M-20M, 24 months to perform, 6-8 months to prepare and submit depending on literature, references and supported by previously submitted "global" supplemental and supportive data from CE Marks, if applicable.

In the next post - more information on SE clearance from FDA/CDRH.

International Clinical Trial Site Inspections by FDA

A question often asked by pharmaceutical sponsors pertains to criteria for assigning inspections at foreign clinical trial sites - what triggers an onsite inspection by FDA CDER? International clinical trial sites will be audited if there is insufficient domestic data supporting a US clinical submission and non-US data becomes primary data and not supplemental or supportive for a drug marketing approval. Inspections are announced by FDA CDER when foreign clinical trial data is submitted for a US marketing application and inconsistencies in domestic and international clinical trial data and documentation are discovered on review. Inconsistencies between domestic and international data will trigger serious issues pertaining to unreported, under-reporting of AEs, data validity, data integrity and quality.

When conflicting data is identified by FDA CDER and when those results are pertinent to decision-making actions impacting resolve, FDA will arrive onsite, announced or unannounced. Refusal to file will be one action taken by FDA, other investigative actions involving suspicion of fraud, clinical, financial or otherwise, scientific misconduct, significant human subject protection violation - penalties, fees, loss of license, imprisonment, other enforcements will be swift and rigorous.

Facts:

• There is a rise is the number of foreign clinical investigators and clinical trial sites inspected in the last 6 years, with 2010 inspections already exceeding those published in 2009
• Clinical inspections by FDA CDER are highest in Europe, South/Central America and Africa, with Asia and the Pacific Rim second, while Eastern Europe was last.

In the last 2 years, non-US clinical site inspections by country:

• Canada 117
• U.K. 92
• Germany 54
• France 54
• Russia 36
• Italy 35
• Sweden 31
• South Africa 30
• Belgium 26
• Poland 22
• Netherlands 21
• Spain 16
• Argentina 16
• Finland 15
• Denmark 14
• Czechoslovakia 13
• Australia 11
• Brazil 11
• ROW country by country less than 10.

www.fda.gov provides lists of clinical investigators who have been disqualified, restricted or provided assurances.

FDA Regulation Regarding Acceptance for Foreign Data for US Marketing Approval

A pharmaceutical sponsor who relies on foreign data from a clinical study to support an Investigational New Drug (IND) application and clinical submission for US marketing approval must adhere to requirements cited in 21 CFR 312(b). The pharmaceutical sponsor must submit the following information to FDA:

• Description of clinical investigator's qualifications
• Description of clinical research facilities
• Description of clinical trial site
• Detailed summary of the clinical study protocol
• Finished, complete, ICH compliant final clinical study report (CSR)
• Patient Case Report Forms (CRFs) maintained by the clinical investigator at the clinical trial site - FDA will request CRFs, often there is a question as to whether a request by FDA will be made - prepare ahead of time - the compilation, collation, collection and submission of CRFs is time and labor intensive - the submitted file must be properly formatted, quality-controlled and quality-assured by qualified documentation experts
• Description of drug product and drug substance including components, formulation, specifications and bioavailability, CMC for starters
• If the clinical study is intended to support effectiveness and safety, the data and documentation must be collected, maintained and managed in accordance with 21 CFR 314.26 GCP.

Regarding Good Clinical Practice and foreign data, GCP must be followed to protect clinical study participants and ensure data and documentation integrity and quality. Final clinical study reports must be prepared in accordance with ICH GCP, including review and approval by an Independent Ethics Committee (IEC). FDA directs the review, inspection efforts and acceptance of foreign clinical study data for marketing approval under the Proposed Rule for Human Subject Protection published June 2004. The rule may be viewed at www.fda.gov/OHRMS/DOCKETS.

Under special consideration, FDA may consider foreign clinical study data to support a marketing approval on its own merit. The criteria for such a marketing application and clinical submission are cited in 21 CFR 314.106(b). Under 21 CFR 314.106(b), foreign clinical study data used to support a marketing application and clinical submission on its own merit must comply with the following requirements:

• Data and documentation are applicable and consistent with US medical practice and population demographics and statistical considerations
• Clinical investigators are qualified
• Data and documentation are of high quality
• Data and documentation are valid without FDA inspection
• Data and documentation are ICH compliant
• Data and documentation are collected under GCP
• Data and documentation are complete, quality-controlled and quality-assured
• Data and documentation are quality managed
• Data and documentation are collected by qualified clinical research associates (CRAs)
• Data and documentation are adequately monitored in accordance with GCP
• FDA may and will inspect the clinical trial site (facility) to ensure validity of data and documentation.

Clinical Submission Approval under FDA Section 505(b)(1)

A clinical submission filed under FDA Section 505(b)(1) is an NDA, is required to demonstrate clinical meaningful treatment benefits and statistically significant safety and efficacy objectives and endpoints, is a new chemical entity, with a new indication. The new investigational drug will be administered to the patient in a new formulation, with a new dosage form, new dose strength and is patented. The pharmaceutical company and/or manufacturer seeks market exclusivity for the NDA. Approval of the NDA under Section 505(b)(1), is granted by FDA only after an extensive Phase 1, 2, 3 clinical development program. When all 3 clinical phases are complete, the pharmaceutical company and/or manufacturer, submits an NDA including all results from all studies, nonclinical, preclinical, CMC, clinical, bioanalytical, pharmacologic and pharmacokinetic to FDA. The NDA is filed, reviewed for filing completeness and then sent to the appropriate division at FDA for review. The regulatory "clock" begins for the file.

An NDA is the culmination of 10-15 years of discovery, R&D, clinical development and by the time an NDA is approved by FDA, the pharmaceutical company and/or manufacturer, has invested numerous years and many millions for the approval. Post-marketing, post-approval is the next step and requires a 12 - 36 month commitment to monitor and assess new drug attributes such as risk, benefit, safety, effectiveness, SAE reports and otherwise. At the time of approval of an NDA, FDA grants a period and right of exclusivity to the submitter for the newly approved drug. The approved drug and patent(s) are protected for up to 20 years from the date of the first filing of the patent application.

Under the Hatch-Waxman Act, a new drug application and clinical submission process will fall into one of two categories depending on drug profile and background. The two categories are NDAs and ANDAs (Abbreviated) New Drug Applications. Under FDA Section 505(b), a new drug application and clinical submission is further divided into Sections 505(b)(1) and 505(b)(2). An ANDA is further delineated with respect to Bioequivalence requirements and is submitted as a 505(j) application and clinical submission. The 505(j) drug moiety is not a new chemical. Pharmaceutical companies and/or manufacturers filing under Section 505(j) must follow the "generic" approval process for drug application and clinical submission.

NDAs and ANDAs require QC and QA to ensure fileability, quality content, accurate, consistent data and documentation and a successful clinical and regulatory approvability outcome with FDA and otherwise. NDAs and ANDAs are submitted in a CTD (Common Technical Document) presentation and format. CTD content, completeness and format must be quality-controlled and quality-assured to ensure regulatory compliance and reviewer friendly dossier navigation. For expert clinical submission service and consultation contactus@danteresources.com, danteresources@yahoo.com.

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.