EMA publishes Q&A on Health Based Exposure Limits – Does the 1/1000 dose criterion come again into play in Cleaning Validation?
In 2014 the European Medicines Agency (EMA) issued the Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. This publication triggered a discussion about the Permitted Daily Exposure (PDE) values in the Pharmaceutical and even in the API Industry, especially regarding crosscontamination and cleaning validation. Now a draft of a Q&A paper from the EMA provides some concretisation.
In 2014 the European Medicines Agency (EMA) issued the Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. As mentioned in the publication itself, this document triggered a discussion about the Permitted Daily Exposure (PDE) values in the Pharmaceutical and even in the API Industry, especially regarding crosscontamination and cleaning validation. Now, the draft of a question & answer paper from the European Medicines Agency provides some concretisation of the guideline.
The document altogether comprises five pages with 14 questions and answers.
The questions – and even more the answers – are very interesting, as shown in question 1 already: Do companies have to establish Health Based Exposure Limits (HBELs) for all products?
The answer is: Yes, but there are references to question 2 and 4 (and their respective answers). Question 2 clarifies what products/active substances are considered as highly hazardous. There are, among others, 5 groups listed, which products should be classified as highly hazardous (e.g.compounds with a high pharmacological potency, daily dose < 1 mg/day (veterinary dose equivalent 0.02 mg/kg)). For highly hazardous substances the answer yes in question 1 is expected. Even more interesting is the link to question and answer 4: Can calculation of HBELs be based on clinical data only (e.g. 1/1000th of the minimum therapeutic dose)? And the answer is yes, but only at designated circumstances. This means the products should have a favourable therapeutic index (safety window) and the pharmacological activity would be the most sensitive/critical effect.
Some further clarification regarding LD 50 is provided in Question 5 and the respective Answer: The use of LD 50 to determine health based limits is not allowed.
There are also more questions and answers regarding Veterinary Medicinal Products, the inspection of the competence of the toxicology expert developing HBELs, Occupational Exposure Limits, cleaning limits, Investigational Medicinal Products and paedric medicinal products and about Cross Contamination. Details will follow.
The document is still a draft and the industry has the opportunity to comment it until the end of April 2017. Let´s see what the final version will bring.
Please also see the draft Questions and answers on implementation of risk based prevention of cross contamination in production and ‘Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities’on the EMA website.
At ECA´s Cleaning Validation Course, 9-10 February 2017 in Heidelberg, Germany the EMA Q&A draft will also be discussed.
///////////EMA, Q&A , Health Based Exposure Limits, 1/1000 dose , criterion, Cleaning Validation,
The new EMA “Guideline on the chemistry of active substances” represents the current state of the art in regulatory practice and fits into the context of the ICH Guidelines Q8-11. Find out what information regarding active substances European authorities expect in an authorization application.
A medicinal product authorization application requires comprehensive information on origin and quality of an active substance. What information is required was defined in two Guidelines so far: the Guideline “Chemistry of Active Substances” (3AQ5a) from 1987 and the “Guideline on the Chemistry of New Active Substances” from 2004. Because both Guidelines’ content do not take into account the ICH Guidelines Q8-11 issued in the meantime and do thus not meet the current state of the art in sciences and in regulatory practice, the EMA Quality Working Party (QWP) developed an updated document entitled “Guideline on the chemistry of active substances” (EMA/454576/2016), which was issued on 21 November.
The new Guideline describes the information on new or already existing active substances required in an authorization dossier. In the context of this Guideline “already existing” ingredients are those that are used in a product already authorized in the EU.
In detail the information and data regarding the substance have to be included in the following chapters of the CTD:
3.2.S.1: Nomenclature, information on the structural formula, pharmacological relevant physicochemical properties.
3.2.S.2: Information on the manufacturer(s), contractor(s), testing facilities etc.; description of the manufacturing processes (schematic representation with flow diagram as well as narrative); where appropriate detailed information on alternative manufacturing processes, for recovering of solvents and for routine reprocessing. Information with regard to re-working should not be included in the authorization dossier.
3.2.S.2.3: Information for controlling the material used during the manufacture and for its specification (incl. identity test). This paragraph is more comprehensive in the new Guideline compared with its predecessor and takes into account the requirements of the ICH Guideline Q11. This Guideline comprises requirements for the following materials: materials from biological sources, those used for the chemical synthesis of starting materials, materials from herbal origin, excipients like solvents (incl. water), reagents, catalysts etc.
3.2.S.2.4: Information on critical process steps (the Guideline comprises examples for these critical steps) as well as on quality and control of isolated intermediates within the synthesis steps. All information has to be provided with the appropriate justifications.
3.2.S.2.5: Information on Process Validation
3.2.S.2.6: Information on the development of the manufacturing process. Here all changes have to be described that were performed during the various phases (pre-clinical, clinical, scale-up, pilot and possibly production phase) of the process for new active substances. For already existing active substances available in production scale no information on process development is needed.
3.2.S.3: Information on Characterisation. Comprehensive information on the elucidation of the structure of the active substance, its physico-chemical properties and its impurities profile have to be provided. Further, the mutagenic potential of degradation products has to be considered. The analytical methods have to be described and their suitability has to be justified.
3.2.S.4: Information on the control of active substances. The analytical procedures and their validation have to be described. Data for the analytical method development should be provided if critical aspects of the analysis regarding the active substance’s specification need to be clarified. Analytical data are necessary for batches for pre-clinical and clinical studies as well as for pilot batches which are not less than 10% of the maximum production scale. The substance’s specification and its control strategy have to be justified on the basis of data from the pre-clinical and clinical phase and, if available, from the production phase.
3.2.S.5: Information on reference materials. If no Chemical Reference Substances (CRS) of the European Pharmacopoeia – counting as completely qualified reference standards – are used, comprehensive information on the analytical and physico-chemical characterization are required even for established primary standards.
3.2.S.6: Information on Container Closure System. Here a brief description is sufficient. However, if a Container-/Closure System is critical for the substance’s quality, its suitability has to be proven and justified. A reference to stability data can be used as supporting information.
3.2.S.7: Information on Stability. A detailed description of the stability studies carried out and the protocol used as well as a summary of the results are expected. Information on stress studies and conclusions on storage conditions and re-test dates or expiry dates are also to be made. This does not apply to substances monographed in the European Pharmacopoeia. If no re-test period or expiry date of batches on the production scale is available at the time of submission of the application, a stability commitment has to be attached with a post-approval stability protocol. The analytical methods have to be described.
The Guideline’s provisions also apply to an Active Substance Master File (ASMF) or to a Certificate of Suitability (CEP). They apply to active substances that have undergone development in a “traditional” way or according to the “enhanced” approach. The provisions of the ICH Guidelines Q8-11 have to be taken into account.
The Guideline is not applicable to active substances of herbal, biological and biotechnological origin as well as to radiolabelled products and radiopharmaceuticals.
The Guideline “Guideline on the chemistry of active substances” (EMA/454576/2016) becomes effective six months after issuing, which means in May 2017.
///////////////EMA, Guideline, chemistry of active substances
|EMA/ FDA Mutual Recognition Agreement moving forward|
|A possible agreement between the EMA and the US FDA on mutual recognition agreement on drug facility inspections could already be signed in January 2017.|
A possible agreement between the European Medicines Agency EMA and the US Food and Drug Administration FDA on mutual recognition of drug facility inspections could already be signed in January 2017. This is noted in a report of the EU Commission: “The state-of-play and the organisation of the evaluation of the US and the EU GMP inspectorates were discussed. In light of the progress achieved, the conclusion of a mutual recognition agreement of Good Manufacturing Practices (GMPs) inspections by January 2017 is under consideration.”
But, according to the Commission, some issues are still not resolved – like, for example, the exchange of confidential information and the inclusion of veterinary products in the scope of the text.
The “Report of the 15th Round of Negotations for the Transatlantic Trade and Invesment Partnership” summaries the 15th round of negotiations for the Transatlantic Trade and Investment Partnership (TTIP) from 3rd to 7th October 2016 in New York.
////////EMA, FDA, Mutual Recognition Agreement, drug facility inspections
One and a half year after its publication, the ICH Q3D guideline still raises many questions. The EMA has recently published a guideline draft aiming at clarifying the practical implementation of ICH Q3D. Read more here about what is expected in a marketing authorisation application or in an application for a CEP with regard to risk assessment and the control of elemental impurities in APIs and medicinal products.
The “ICH Q3D Guideline for Elemental Impurities” was published in December 2014 as Step 4 document and released in August 2015 under No EMA/CHMP/ICH/353369/2013 as EMA’s Scientific Guideline. The guideline came into effect in June 2016 for all medicinal products currently underlying a marketing authorisation procedure (new applications).
In the meantime, it became clear that implementing in practice the requirements of this guideline has been so complex and led to some marketing authorisation procedures being delayed. The ICH has already reacted to the situation and published 7 training modules on its website. Moreover, a concept paper announces a question & answer document.
On 12 July 2016, the draft of an EMA’s guideline entitled “Implementation strategy of ICH Q3D guideline” (EMA/404489/2016) was published. The purpose of the document is to provide support for implementing ICH Q3D in the European context.
The draft comprises three chapters addressing the most important elements in relation with the implementation of the ICH Q3D requirements. The chapter “1. Different approaches to Risk Management” starts describing the two fundamental approaches to the performance of a risk assessment and the justification for a control strategy with regard to elemental impurities:
Drug Product Approach
Here, batches of the finished product are scanned by means of analytical (validated!) procedures to develop a risk-based control strategy. If – with this approach – the omission of a routine testing has to be justified, the authority expects a detailed and valid justification though, and not just analytical data from a few batches.
The guideline draft clearly gives its preference to this approach. The respective contribution of the different components of a medicinal product is considered with respect to the potential total impurity profile and compared to the PDE value from the risk assessment. All potential sources of impurity, for example from production equipment or from excipients of natural (mined) origin have to be considered in this assessment. This particularly applies to outsourced APIs; here, all pieces of information available from Active Substance Master Files (ASMFs) or Certificates of Suitability (CEPs) have to be used. Substances with a Ph.Eur. monograph should always comply with the elemental impurities limits of the corresponding monograph.
The chapter “2. Particulars for Intentionally Added Element(s)” deals with the common practice in many organic syntheses to add elements to increase the specificity of the chemical reaction and the yield. It is particularly critical when the last step of an API synthesis just before the end product uses a metal catalyst. In such a case, the authority expects a convincing evidence that the catalyst is purged to levels consistently below the control threshold (<30% of the PDE) by means of appropriate methods. All details about the API synthesis including the fate of the metals intentionally added have to be consistently described and documented in the marketing authorisation application or in the application for a CEP. If the routine testing of an elemental impurity is needed, the API manufacturer may determine a specification. This information will be required by the medicinal product manufacturer for his overall risk assessment.
The chapter “3. ASMF/CEP: dossier expectations and assessment strategy” explains who has to submit the risk assessment necessary for an ASMF or a CEP and how the dossier will be processed by the assessor of the regulatory authority. Basically, two scenarios are possible:
1. The API manufacturer submits a summary of a risk assessment/management for elemental impurities
Such information flows in the overall risk assessment of the medicinal product manufacturer and is assessed by the quality assessor/ CEP assessor within the marketing authorisation procedure. All data and documents used for the risk assessment should also be available for a GMP inspection.
2. The API manufacturer doesn’t perform any risk assessment/ management.
The regulatory authority basically expects a detailed description of the API synthesis including data on all metal catalysts used. This as well as the analytical routine controls on elemental impurities performed by the API manufacturer will also be assessed by the quality assessor/ CEP assessor. Nevertheless, the assessor won’t make a final conclusion in the ASMF or CEP assessment report with regard to the compliance with ICH Q3D. This will be done within the marketing authorisation procedure for the medicinal product.
The guideline draft can be commented on until 12 August 2016.
///////////ICH Q3D, Control of Elemental Impurities, EMA, control of elemental impurities in APIs
Following the issuance of two Non-Compliance Reports for two sites of the US based company, EMA has started a review of medicines manufactured by Pharmaceutics International Inc., USA.
The European Medicines Agency (EMA) has started a review of medicines manufactured by Pharmaceutics International Inc., USA. This follows the issuance of two Non-Compliance Reports for two sites of the US based company after an inspection in February 2016 conducted by the MHRA (the medicines regulatory agency in the United Kingdom) which highlighted several shortcomings in relation to good manufacturing practice (GMP).
Pharmaceutics International Inc. manufactures the centrally authorised medicine Ammonaps (sodium phenylbutyrate) and is also the registered manufacturing site for some other medicines that have been authorised through national procedures in the European Union (EU).
This inspection which was a follow-up to an inspection in June 2015 aimed to assess whether corrective measures agreed previously had been appropriately implemented. It found that shortcomings remained, which included insufficient measures to reduce the risk that traces of one medicine could be transferred to another (cross-contamination), as well as problems with the way data were generated and checked and deficiencies in the systems for ensuring medicines’ quality (quality assurance).
EMA’s Committee for Medicinal Products for Human Use (CHMP) will now review the impact of the inspection findings on the products’ overall benefits and risks and make a recommendation as to whether any changes are needed to their marketing authorisations.
There is no evidence that patients have been put at risk by this issue. However, as a precautionary measure, medicines from this site will no longer be supplied to the EU unless they are considered to be ‘critical’ to public health. Criticality will be assessed by national medicines regulatory agencies for their territories, taking into account alternatives and any impact of shortages on patients. In case where a medicine manufactured at this site is considered not critical in a member state it will no longer be supplied in this member state and any medicine remaining on the market will be recalled.
Source: EMA Press Release
/////////// EMA, Medicines, manufactured, U.S. Company, Pharmaceutics International Inc., USA
Regulatory Approval Pathways: EU vs US
Drug Authorization Procedures in the EU
Sponsors have several options when seeking market approval for a new drug in Europe: a national authorization procedure, a decentralized procedure, a mutual recognition procedure and a centralized procedure. Depending on a product’s eligibility, each of these authorization routes offers different advantages and disadvantages to the sponsor, and these should be considered when setting up the market strategy of a product.
This procedure is used whenever a company wants to commercialize a product in only one EU Member State.
The National procedure is specific to each country. That is, each country within the EU has its own procedures for authorizing a marketing application for a new drug. Sponsors can find information regarding the requirements and procedure of each country on the websites of the regulatory agencies.
ADVANTAGES of National Procedure
There are some advantages in submitting a MAA through this procedure. First, it allows the sponsor to choose which country the company will submit to first. This is especially advantageous when the sponsor can’t afford to go through the centralized or decentralized procedure, due to lack of resources of distribution infrastructure for example. Choosing the country that the sponsor is most familiar with in regards to its regulation can also be an important factor. The national authorization procedure also allows the sponsor to, further down the line, get his drug approved through the mutual recognition procedure, seeing as one country already approved its drug. Overall, this procedure is less resource heavy than the others, and thus it is the cheapest and safest alternative for a sponsor.
DISADVANTAGES of National Procedure
The disadvantages are obvious, seeing as this procedure only allows the sponsor to commercialize in one single market, cutting potential revenue streams it could have by bringing the drug to more markets.
The centralized procedure is a Europe wide authorization procedure, conducted by EMA’s Committee for Human Medicinal Products (CHMP), an organization which has representatives of all Member states, EEA members, patient organizations and health professionals.
When a sponsor applies for drug approval through the Centralized Procedure, two member states are first selected, a rapporteur and a co-rapporteur. These two member states will be responsible for the creation of an evaluation report that will be assessed by the CHMP. First, a draft report is prepared and sent to the committee for review. The committee prepares a set of questions to send to the sponsor. After receiving a response, further discussions continue and a final evaluation report is arranged, containing a positive or negative opinion. This whole process can take up to 210 days. After the report is completed, it is sent to the European Commission in less than 15 days. The European Commission has the final say on the matter, granting the MA or not after evaluation of the CHMP’s report. The EC’s decision is applicable to all Member States of the European Union and EEA states – Iceland, Norway e Liechtenstein. After approval from the EC, the MA is valid for five years.
The centralized procedure, when it was introduced by Regulation (EEC) no 2309/93, followed the footsteps first established by Directive 87/22/EEC with its concertation procedure , and it was first made obligatory to products made from Recombinant DNA technology, controlled gene expression and monoclonal antibodies.
Afterwards, Regulation (EC) No 726/2004 extended the scope of the procedure to include orphan medicinal products and new active substances for the treatment of acquired immune deficiency syndrome (HIV), cancer, neurodegenerative disorder or diabetes. It went into force in 20th November 2005.
Recital 8 and Point 3 of the Annex to Regulation (EC) No 726/2004 also established that, starting 20 May 2008, the centralized procedure would be obligatory for drug products containing new active substances for the treatment of autoimmune diseases and other immune dysfunctions and viral diseases.
Lastly, regulation EC No 1394/2007 made the procedure compulsory for Advanced Therapy Medicinal products, like gene therapy, tissue engineered and somatic cell therapy products.
Article 3(2) of Regulation (EC) No 726/2004 defines the optional scope of the centralized procedure. It states that the procedure can be followed optionally by medicines that contain a new active substance, or if the applicant shows that the therapeutic entity provides a significant therapeutic, scientific or technical innovation, and it would be in the best interest of public health if it was approved at a community level.
ADVANTAGES of Centralized Procedure
Products authorized through the centralized procedure are granted marketing authorizations that cover all EU member states and the EEA, a big, 500 million user market where the sponsor can potentially recoup the losses from drug development. The drug will be commercialized in all countries with a single, unique brand name.
The convenience of the centralized procedure is however accompanied by fees that are significantly higher than the national procedure’s.
DISADVANTAGES of Centralized Procedure
Also, it is also a very risky, all or nothing procedure. If the CHMP refuses an application, the drug is barred from sale in every EU country, whereas if the sponsor tried another authorization procedure, there was the possibility of getting approval in at least one country. Since the sponsor can’t choose the rapporteur countries like he can in other procedures, this also leaves him at a disadvantage.
Mutual Recognition Procedure
This procedure requires the drug to be already approved in a MS.
This procedure is based upon the principle that a marketing authorization and the evaluation in one Member State (the so-called reference Member State) ought to be recognized by the competent authorities of the other Member States (the so-called concerned Member States), that is, if a Member State concedes a national MA to a drug, other Member States can recognize the evaluation conducted by it and grant a MA for the drug themselves.
It’s also noteworthy to point out that both a Member State and the Sponsor can trigger the Mutual Recognition Procedure.
After the first marketing authorization in the Community is granted, the marketing authorization holder may request one or more Member State(s) to recognize an authorization approved by the reference Member State, by submitting an application in accordance with Article 28 of Directive 2001/83/EC.
Within 90 days of receipt of a valid application, the reference Member State will provide the assessment report together with the approved summary of product characteristics, labeling and package leaflet to the concerned Member States and to the marketing authorization holder.
Within 90 days of the receipt of these documents, the concerned Member States shall recognize the decision of the reference Member State and the approved summary of product characteristics, package leaflet and labeling by granting a MA.
If any country refuses to grant a MA by safety reasons, the matter will be taken to The Co-ordination Group for Mutual Recognition and Decentralized Procedures, which will attempt to make all member states reach a consensus in 60 days. If it fails, the request will be taken to the CHMP and treated like a centralized procedure.
The decentralized procedure works in a similar way as the mutual recognition one, except here the medicinal product in question has not yet received a marketing authorization in any Member State at the time of application. Like the MRP, a reference member state is chosen, which will evaluate the MAA. The remaining member states then proceed to give their opinion on the evaluation. If all concerned member states agree on the evaluation by the reference member state, the drug will be approved and allowed for sale in those countries. If a member state disagrees, the Co-ordination Group for Mutual Recognition and Decentralized Procedures will, like in the MRP, play a referee role.
ADVANTAGES and DISADVANTAGES of MRP & Decentralized Procedure
Both the MRP and the decentralized procedure carry a set of advantages and disadvantages that sponsors ought to know before setting their product market strategy. Both of them allow a sponsor to avoid the need to go through different national procedures in each country. Moreover, they aren’t as risky as the centralized procedure, and, in the case of the MRP, the sponsor can choose the reference member state that will conduct the evaluation of the drug product (by first attaining a MA in that country). In both these procedures, fees have to be paid to all Member states who participate in the process, and, unlike the centralized procedure, the sponsor may have to attribute a different name for its drug product in different Member States., which may hurt brand awareness.
The MRP often sees disagreements between member states, holding up the procedure and causing delays. In these occasions, a lengthy dispute solving mechanism has to be employed, costing both time and money to the sponsor
The decentralized procedure avoids some of the potential disputes between member states by engaging each of the member states the applicant wishes to apply to at the time the first marketing authorization is made. Disputes are this less common in the decentralized procedure than in the MRP. Lastly, the decentralized procedure is faster than the MRP. The first can take up to 210 days to complete its two steps. The MRP, on the other hand, a national MA is first needed, which can take up to 210 days, alongside the update period of the MA license before the MRP procedure starts proper, which can take more 180 days. The take home message is that there is no one-size fits all in regards to drug authorization procedures. Each one of the four available has different advantages and disadvantages, which have to be carefully weighed out by the sponsor.
Drug Approval Process for the US
Types of Applications Submitted to the US FDA for New Medicines/Treatments
Investigational New Drug (IND) – Federal law requires that a drug be the subject of an approved marketing application before it is transported or distributed across state lines.
New Drug Application (NDA) – When the sponsor of a new drug believes that enough evidence on the drug’s safety and effectiveness has been obtained to meet FDA’s requirements for marketing approval, the sponsor submits a new drug application (NDA) to FDA. The application must contain data from specific technical viewpoints for review, including chemistry, pharmacology, medical, biopharmaceutics, and statistics. If the NDA is approved, the product may be marketed in the United States.
Biologic License Application (BLA) – Biological products are approved for marketing under the provisions of the Public Health Service Act. The Act requires a firm who manufactures a biologic for sale in interstate commerce to hold a license for the product. A biologics license application is a submission that contains specific information on the manufacturing processes, chemistry, pharmacology, clinical pharmacology and the medical effects of the biologic product. If the information provided meets FDA requirements, the application is approved and a license is issued allowing the firm to market the product.
US Drug Approval Process
If an IND drug survives the clinical trials (phase 1-3), an NDA is submitted to the FDA. An NDA contains all the preclinical and clinical information obtained during the testing phase. The application contains information on the chemical makeup and manufacturing process, pharmacology and toxicity of the compound, human pharmacokinetics, results of the clinical trials, and proposed labeling. An NDA can include experience with the medication from outside the United States as well as external studies related to the drug.
After receiving an NDA, the FDA completes an independent review and makes its recommendations. The Prescription Drug User Fee Act of 1992 (PDUFA) was designed to help shorten the review time. This act allowed the agency to collect user fees from pharmaceutical companies as financial support to enhance the review process. The 1992 Prescription Drug User Fee Act (PDUFA) established a two-tiered system – Standard Review and Priority Review.
Standard Review is applied to a drug that offers at most, only minor improvement over existing marketed therapies. The 2002 amendments to PDUFA set a 10 month goal for a standard review.
Priority Review designation is given to drugs that offer major advances in treatment, or provide a treatment where none existed. The goal for completing a Priority Review is six months.
If during the review the FDA staff feels there is a need for additional information or corrections, they will make a written request to the applicant. During the review process it is not unusual for the FDA to interact with the applicant staff.
The following four FDA programs are intended to facilitate and expedite development and review of new drugs to address unmet medical need in the treatment of a serious or life-threatening3 condition: fast track designation, breakthrough therapy designation, accelerated approval, and priority review designation.
Drug development in the fast lane: FDA approaches to expedited approval.
Fast track designation applies to the drug (either alone or in combination with other drugs) and the specific use for which it is being studied. The term drugrefers to the combination of two or more drugs if the combination is the subject of the fast track designation or request. Where appropriate, FDA may grant designation to the development of a new use of an approved drug.
- Serious Condition
- Demonstrating the Potential to Address Unmet Medical Need
The type of information needed to demonstrate the potential of a drug to address an unmet medical need will depend on the stage of drug development at which fast track designation is requested. Early in development, evidence of activity in a nonclinical model, a mechanistic rationale, or pharmacologic data could be used to demonstrate such potential. Later in development, available clinical data should demonstrate the potential to address an unmet medical need.
BREAKTHROUGH Therapy Designation
Section 506(a) of the FD&C Act provides for designation of a drug as a breakthrough therapy “. . . if the drug is intended, alone or in combination with 1 or more other drugs, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on 1 or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.” It is important to recognize that the standard for breakthrough therapy designation is not the same as the standard for drug approval. The clinical evidence needed to support breakthrough designation is preliminary. In contrast, as is the case for all drugs, FDA will review the full data submitted to support approval of drugs designated as breakthrough therapies to determine whether the drugs are safe and effective for their intended use before they are approved for marketing.
The accelerated approval provisions of FDASIA in section 506(c) of the FD&C Act provide that FDA may grant accelerated approval to:
. . . a product for a serious or life-threatening disease or condition . . . upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.
For drugs granted accelerated approval, post marketing confirmatory trials have been required to verify and describe the anticipated effect on IMM or other clinical benefit
Post marketing surveillance is important, because even the most well-designed phase 3 studies might not uncover every problem that could become apparent once a product is widely used. Furthermore, the new product might be more widely used by groups that might not have been well studied in the clinical trials, such as elderly patients. A crucial element in this process is that physicians report any untoward complications. The FDA has set up a medical reporting program called Medwatch to track serious adverse events (1-800-FDA-1088). The manufacturer must report adverse drug reactions at quarterly intervals for the first 3 years after approval, including a special report for any serious and unexpected adverse reactions
Regulatory Links for the US FDA Guidances
Guidance for Industry -Expedited Programs for Serious Conditions – Drugs and Biologics, May 2014
Good Review Practice: Refuse to File, available on the Internet at http://www.fda.gov/downloads/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/manualofpoliciesprocedures/ucm370948.htm and CBER SOPP 8404, Refusal to File Procedures for Biologic License Applications (August 27, 2007), available on the Internet athttp://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ProceduresSOPPs/ucm073474.htm.
Regulatory Links for the EU:
Directive 2001/20/EC of the European Parliament and of the Council of 4 April2001 on the approximation of the laws, regulations and administrative provisions of the MS relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. http://eur-lex.europa.eu/LexUriServ/LexUriServ.douri=OJ:L:2001:121:0034:0044:en:PDF
Detailed guidance on the request to the competent authorities for authorization of a clinical trial on a medicinal product for human use, the notification of substantial amendments and the declaration of the end of the trial (CT-1) (2010/C 82/01) http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:C:2010:082:0001:0019:
EFPIA: Status of the implementation of the European Union Clinical Trials
Directive at member state level, Circular N° 12.784 , June 2008
Klingmann I et al. Impact on Clinical Research of European Legislation. Final report, February 2009http://www.efgcp.be/downloads/icrel_docs/Final_report_ICREL.pdf
Assessment of the functioning of the “Clinical Trials Directive” 2001/20/EC, Public Consultation Paper, ENTR/F/2/SF D(2009) 32674http://ec.europa.eu/enterprise/sectors/pharmaceuticals/files/clinicaltrials/docs/2009_ 10_09_public-consultation-paper.pdf
Report of the multidisciplinary workshop on “A single CTA in multinational clinical trials – dream or option?”, Brussels, Belgium, 7 July 2009http://www.efgcp.be/Conference_details.asp?id=265&L1=10&L2=2&TimeRef=2
Clinical Trials Facilitation Groups, Guidance document for a VoluntaryHarmonization Procedure (VHP) for the assessment of multinational Clinical Trial Applications, Version 2 ; Doc.ref.: CTFG/VHP/2010/Rev1, March 2010 http://www.hma.eu/uploads/media/VHP_version_2_March_2010.pdf
European Commission Enterprise Directorate-General. Detailed guidance on the application format and documentation to be submitted in an application for an Ethics Committee opinion on the clinical trial on medicinal products for human use (ENTR/CT2), Revision 1, February 2006http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-10/12_ec_guideline_200 60216.pdf
The EFGCP Report on The Procedure for the Ethical Review of Protocols forClinical Research Projects in Europe, Update April 2010http://www.efgcp.be/EFGCPReports.asp?L1=5&L2=1
European Commission-European Medicines Agency Conference on the Operation of the Clinical Trials Directive (Directive 2001/20/EC) and Perspectives for the Future, Report on the Conference held on 3 October 2007 at the EMEA, London, Doc. ref.: EMEA/565466/2007http://www.eortc.be/services/doc/EUCTD/EC-EMEA_report_CT_20071003.pdf
Assessment of the functioning of the “Clinical Trials Directive” 2001/20/EC,Summary of responses to the public consultation paper, SANCO/C/8/SF/dn D(2010) 380240http://ec.europa.eu/enterprise/sectors/pharmaceuticals/files/clinicaltrials/2010_03_30_summary_responses.pdf
Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community Code relating to Medicinal Products for Human Use, as amendedhttp://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-1/dir_2001_83/dir_2001 _83_de.pdf
Responses to the Public consultation paper “Assessment of the functioning of the ‘Clinical Trials Directive’ 2001/20/EC”, March 2010http://ec.europa.eu/enterprise/sectors/pharmaceuticals/human-use/clinicaltrials/ developments/responses_2010-02_en.htm
Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2007:324:0121:0137:
Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorization of the manufacturing or importation of such products http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2005:091:0013:0019:
European Commission, Impact Assessment, 2010 Roadmaps “Legislative proposal on a Regulation/Directive amending the Clinical Trials Directive 2001/20/EC”, Version 2, 23/03/2010http://ec.europa.eu/governance/impact/planned_ia/docs/47_sanco_clinical_trials_directive_en.pdf
//////////Regulatory Approval Pathways, EU vs US
Sometimes a clear definition of terms is crucial in the communication between authorities and pharmaceutical companies. Find out what the European Medicines Agency EMA defines as “complex manufacturing steps” and what authorisation holders providing a variation application need to consider.
The Variations Regulation (EC) no. 1234/2008 of the European Commission defines the procedure for variations of existing marketing authorisations. The “detailed guidelines for the various categories of variations“, which were published in the consolidated version in August 2013 in the European Official Journal, explain the interpretation and application of this Variations Regulation.
Although the “detailed guidelines” describe a number of scenarios of possible variations in some detail, there are formulations in the Guideline text which require clarification due to their blur. The EMA adopted such a case in a recent update of itsquestions and answers collection “Quality of Medicines Questions and Answers: Part 1” to concretise the case through a statement.
It is about the term “complex manufacturing processes”, which is used in two scenarios associated with type II variations (found in the “detailed guidelines” p 40ff):
- Replacement or addition of a manufacturing site for part or all of the manufacturing process of the finished product (Guideline change code B.II.b.1)
c) Site where any manufacturing operation(s) take place, except batch release, batch control, and secondary packaging, for biological/immunological medicinal products, or for pharmaceutical forms manufactured by complex manufacturing processes.
- Change in the batch size (including batch size ranges) of the finished product (Guideline change code B.II.b.4)
d) The change relates to all other pharmaceutical forms manufactured by complex manufacturing processes .
The EMA now clarified this term as follows:
- Guideline Change Code B.II.b.1: Complex manufacturing processes are given when the understanding of the relation between quality characteristics of the product and its in vivo efficacy is lacking. This is often the case in innovative medicines such as products of nanomedicine.
- Guideline Change Code B.II.b.4: Complex manufacturing processes are those which contain one or more sub-steps, where a scale-up can lead to problems.
In both scenarios, the approving authority will decide on a case by case basis. If the applicant submits the variation as a Type IB, he must provide a valid justification that the production process is not “complex”. However, in doubt the authority may upgrade the variation to a Type II. Therefore, the EMA recommends that the applicant clarifies the situation with the authority before submitting the variation